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At AACR, MSK Researchers Spotlight Health Disparities and Propose Solutions – On Cancer – Memorial Sloan Kettering

Posted: April 19, 2022 at 2:25 am

Among the topics discussed at this years annual meeting of the American Association for Cancer Research (AACR) was disparities in cancer care. Several MSK researchers presented research that directly addresses these problems.

In a prerecorded presentation, MSK physician-scientist Sana Raoof explained how clinical trials of liquid biopsies a type of blood test for cancer can include concrete measures to reduce disparities related to access and inclusion.

Dr. Raoof said such trials should aim to include at least 25% of participants who are non-white a figure that more accurately represents the percentage of non-white individuals in the U.S. population. Previous liquid biopsy trials have included 4% to 13% non-white participants.

The lack of representation of minorities is a huge problem in cancer clinical trials, Dr. Raoof says. Its not just a problem because its unfair and inequitable; its also a problem because it affects scientific conclusions.

To improve access to liquid biopsy trials, academic medical centers should seek to partner with community hospitals that see a more diverse patient population, she says.

Liquid biopsies may aid in early detection because they could potentially be administered in a primary care physicians office, rather than at a cancer center, where most imaging scans and other tests are performed.

In the context of the COVID, were seeing later and later stages at diagnosis across multiple types of cancer, Dr. Raoof says. People are missing their cancer screening tests and are therefore being diagnosed when they have symptoms at later stages, when its harder to cure the disease. That is particularly affecting minorities who, at baseline, have worse access to healthcare.

The lack of representation of minorities is a huge problem in cancer clinical trials.

Sana Raoof, MD, PhD physician-scientist

It would be very useful, Dr. Raoof continues, if we had a point-of-care test that was convenient, quick, and cheap that could be used by everyone but might be of particular benefit to minorities to supplement cancer screening.

Dr. Raoof wrote an editorial about the potential of liquid biopsies to address disparities in access in the Boston Globe last year.

MSK computational oncologist Francisco Sanchez-Vega is part of a team that has for a number of years been studying the genomics of colorectal cancer, trying to identify genomic features that correlate with worse outcomes. They are mining the wealth of genomic data obtained from MSK-IMPACT, a gene-sequencing panel that looks for cancer-associated mutations in 500+ genes.

While doing this work, Dr. Sanchez-Vega noticed that, on average, African American patients in the MSK-IMPACT cohort had worse outcomes compared with other patients. The question that he and others want to understand is why.

The general belief is that this disparity is probably driven by socioeconomic factors, differences in risk factors, differences in access to healthcare, maybe differences in environmental exposure, lifestyle, diet, etc., Dr. Sanchez-Vega says. But we had a very good opportunity to try to understand if there were any genomic features that could at least partially explain these differences or give some insight into these differences.

In his presentation at AACR, Dr. Sanchez-Vega discussed the various genomic factors that they measured, including tumor mutation burden, location of the tumor, and frequency of various oncogenes. The study population included 3,963 patients with colorectal cancer treated at Memorial Sloan Kettering Cancer Center (MSK), including 336 (8%) self-reported Black patients and 3,627 (92%) self-reported white patients.

They found some differences. For example, right-sided colon tumors were more common among Black patients (37% versus 25% in white patients). Hypermutated tumors, including tumors with a condition called microsatellite instability, were more frequent among white patients (12% versus 8% in Black patients).

Tumors in Black patients were enriched in KRAS mutations (60% versus 45% in white patients), but high-risk KRAS-G12C mutations accounted only for 3% of all driver KRAS mutations in Black patients versus 8% of all driver mutations in white patients.

When the investigators factored in all these genomic and clinical differences, however, they still did not explain the difference in outcomes between the two groups namely, that Black patients had shorter overall survival from the time of sequencing (median 28months versus 50months for white patients). This was true even though all patients were treated at the same single institution (MSK) during the study.

Dr. Sanchez-Vega cautions that these results may not apply behind the specific cohort of people who came to MSK, since this population may not be fully representative of the wider community. Nevertheless, the results would seem to point to other factors beyond genomic ones to explain these disparities in outcomes.

For certain types of cancer, knowing ones precise genetic ancestry can be important for properly assessing genetic risk factors for the disease and weighing possible treatments. Perhaps the best example of this phenomenon is people with Ashkenazi Jewish European ancestry, who have a much higher risk of carrying a high-risk BRCA1 or BRCA2 mutation than the general population. These mutations put one at risk for hereditary breast, ovarian, prostate, and pancreatic cancers.

Traditionally, establishing someones genetic ancestry required looking at genetic markers from across the entire genome. At AACR, computational biologists Kanika Arora, Michael Berger, and their colleagues in the Marie-Jose and Henry R. Kravis Center for Molecular Oncology presented their work showing that data from MSK-IMPACT which sequences only a subset of genes in the human genome can be used to reliably establish someones genetic ancestry.

The finding raises the possibility that genetic ancestry testing could be incorporated into routine clinical care whenever a test such as MSK-IMPACT is administered. The potential benefits include a more accurate genetic risk assessment than self-reported race.

A lot of times in medicine, self-reported race is used as a substitute for genetic ancestry, but its not always a good indication of someones actual genetics, explains Arora. For example, someone who identifies as Black could have close to 100% African ancestry, or they could have 50% or less African ancestry. So, while both are Black, self-reported race does not always capture the genetic component well, which is why for certain questions about risk factors, its important to look in detail at measures of ancestry.

A lot of times in medicine, self-reported race is used as a substitute for genetic ancestry, but it's not always a good indication of someone's actual genetics.

Kanika Arora computational biologist

According to the investigators, one particularly noteworthy finding to emerge from their analysis is a discrepancy in the rates of clinically actionable alterations in patients of African ancestry versus patients of European ancestry as determined by MSKs OncoKB database. While the overall proportion of biologically relevant driver mutations was similar between the two groups, patients of African ancestry had, on average, fewer options for drugs matching those mutations.

There are likely several reasons for that, Dr. Berger says, including the fact that genomic-sequencing panels themselves are skewed toward the genomic data collected from largely European populations.

Regardless of the reason, the data would seem to call for more equitable drug development programs, he notes. Patients with African ancestry are not as well served as people with European ancestry by our current precision oncology therapies, Dr. Berger says.

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Designer future: Human intervention is crossing the line of creation – The Poly Post

Posted: April 19, 2022 at 2:25 am

By Brandon Diep, Apr. 12, 2022

What would you change about yourself? Would you change your eye color, hair type, height or the sound of your voice? Maybe you want to become smarter? Funnier? Imagine you could. With human genetic engineering, all the physical and mental traits you desire could become a reality. The only question is: is it morally right?

I believe gene editing or engineering should only be used to cure illnesses and diseases. Designer babies, the ability to change the superficial features of a child, are unethical and should not be conducted. Humans should not change the physical and mental characteristics of their children, but love them as they are.

Human genetic engineering is already possible, and it will soon change the way we think of childbirth and human health. Using a technology called CRISPR, also known as Clustered Regularly Interspaced Short Palindrome Repeats, which is defined by Live Science as, a powerful tool for editing genomes, meaning it allows researchers to easily alter DNA sequences and modify gene function, humans will then have the ability to aesthetically edit the genetic characteristics of an unborn child.

This technology holds unimaginable possibilities. As reported by Tides, a social charity foundation, a person can give a fertility clinic a checklist of characteristics and features they want for their child, scientists then use CRISPR to edit the genes of an embryo accordingly, implant the embryo into the mother for pregnancyand finally, the designer baby is born.

Gene editing was developed for the eradication of diseases and curing of cancer, but it can also be used for creating the child of your dreams. The science is unbelievable and is already being used in controversial ways.

On Nov. 25, 2018, the impossible became possible. A biophysics researcher from China, He Jiankui, shocked the world with the first gene-edited humans. He revealed that he had altered embryos for seven couples during fertility treatmentswith one resulting pregnancy. He was trying to bestow a trait that few people naturally have an ability to resist future infection of HIV, the AIDS virus, according to Associated Press.

Babies Lulu and Nana were the results of Hes gene-editing experiment. Born from an HIV-positive father and HIV-negative mother, the twins are now resistant from contracting the illness their father has. Controversy soon followed the researcher. He is scrutinized by the public for conducting the experiment in secret. Some praised him and called He, the rogue scientist, Chinas Dr. Frankenstein, and a mad genius, as written in the South China Morning Post. The Peoples Court of Shenzhen disagreed with his work, they sentenced him to three years of imprisonment and held him financially responsible for any future genetic complications that might occur in the babies lives. He may have had the best intentions, but he crossed the line of regulated science.

Although Lulu and Nana are the first of many genetically engineered human experiments, gene editing has shown its benefits. The tool has unveiled great opportunities in correcting the course of unfair diseases placed in humans. However, the regulation of gene editing should be a high priority.

The ethics of designer babies needs to be debated. I believe gene editing could negatively affect our future if it is used to aesthetically change children. U.S. News found in 2021 that there are companies offering parents the means of selecting better embryos, although in the form of superficial features has yet to be done. There are some who may use genetic engineering virtuously to prevent hereditary diseases while there are others who may abuse gene editing to design their child with the best attributes. I think it is likely that people will create humans with perfect symmetrical faces and ideal physiques for sports. A child will unfortunately grow up to think that their physical features are what creates their success. These exploitative fantasies could be manipulated into actuality.

Gene editing might also cause major repercussions for religion. There may be some who will find gene editing of a persons exterior to be a defiance against Gods creation. A few branches of Judaism prohibits members from trimming their hair because their body belongs to God and therefore they cannot alter it. I do believe there is a higher being and even though I dont practice this rule, I understand the sentiment. Like many religions, I hold the strong belief that one should not change themselves outwardly but inwardly. Changing the body of a healthy child before they are born is disrespectful toward their creator and their lineage.

Parents considering changing their children to look different from them is also flawed. The traits inherited from previous generations should not be seen as ugly or a mistake. This mindset will only further indoctrinate artificiality and self-hatred into future generations. We all hold a part of our parents within ourselves, we cannot let that go. If we change these genetics, then we are changing something special that connects us with our family. Your genetic material is inherited from hundreds to thousands of previous generations. Genetically modifying it for a superficial reason would counter all of the meaning and history behind that from your ancestors. The gifts of our familys pasts remind us of who were from.

The future reaps the consequences of today. Gene editing is still in its infancy. Going forth with designer babies may give birth to abominable effects on our descendants. One enhancement to the length of our arms could inadvertently mutate the body in a harmful way unknowingly passed down the generations. The harm would only be discovered after it is too late. It is too risky to change the genetic makeup of the most precious thing in life: ourselves.

What needs to be changed is our mentality. Our different eye colors, curly or straight hair, tall or short limbs arent what make us. The power to change these superficial features will not help. As humans, we should not change our children to conform to body standards, but instead, change body standards to conform to us. When you can stop caring about vain appearances, it is only then that we can start caring about what matters. Whats important are the things youve done and the things you are going to do. You arent your body, a shell your soul was born in. You are only who you think you are.

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Being unable to feel pain is not a good thing – The Star Online

Posted: April 19, 2022 at 2:25 am

Patrice Abela first knew something was wrong when his eldest daughter was learning to walk and her feet left trails of blood behind her, yet she showed no sign of distress.

She was soon diagnosed with congenital insensitivity to pain (CIP), an extremely rare and dangerous genetic disorder that dooms sufferers to a lifetime of hurting themselves in ways they cannot feel.

Abela, a 55-year-old software developer in the southern French city of Toulouse, then watched in horror as his youngest daughter was revealed to have the same condition.

Now aged 12 and 13, the two girls spend around three months of every year in hospital.

When they take a shower, they perceive hot and cold, but if it burns, they dont feel anything, said the father of four.

Due to repeated infections, my eldest daughter lost the first joint of each of her fingers.

She also had to have a toe amputated.

Repeated knee injuries have left both girls only able to move around using crutches or a wheelchair.

Abela said they may not feel physical pain, but lamented their intense psychological pain.

Aiming to raise awareness about the disease and challenge the scientific community, Abela plans to run the equivalent of 90 marathons in fewer than four months.

He started on April 12 (2022), following the route of this years Tour de France from Copenhagen to Paris.

A life without pain might sound like a dream come true, but the reality is more like a nightmare.

There are only a few thousand known cases of the condition worldwide.

The low number is believed to be partly due to sufferers often not living into adulthood.

Pain plays a major physiological role in protecting us from the dangers of our environment, said Dr Didier Bouhassira from the centre for pain evaluation and treatment at Ambroise-Pare hospital in Paris, France.

In the most extreme cases, babies will mutilate their tongue or fingers while teething, he said.

Then comes a lot of accidents, burns, walking on fractured limbs which heal badly, he said.

They have to be taught what is innate in others: to protect themselves.

But when there are no warning signs, danger lurks everywhere.

Appendicitis, which announces itself in others via symptoms like pain and fever, can fester into a devastating general infection of the abdomen.

Blindness can also occur because the eye must always be kept moist and the nervous system controls these processes via the so- called blink reflex, said Professor Dr Ingo Kurth of Germanys Institute of Human Genetics.

CIP was first recognised in the 1930s, and numerous studies have since identified a genetic mutation that blocks a persons ability to feel pain.

We have now learned that there are more than 20 genetic causes of congenital or progressive insensitivity to pain, Prof Kurth shared.

There is no cure and no real drug breakthroughs have been made so far, he added.

But our understanding of the molecular causes of CIP continues to reveal new targets, and based on this, hopefully new therapies will be developed in the coming years.

There are also hopes that studying how CIP works could lead to the development of a new kind of painkiller, prompting huge interest from pharmaceutical giants seeking a fresh product in the billion-dollar industry of pain relief.

In this way, the unlucky few with CIP could contribute to the creation of a treatment that would help everyone in the world -- except themselves. AFP Relaxnews

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This Native American Tribe Wants Federal Recognition. A New DNA Analysis Could Bolster Its Case – Smithsonian Magazine

Posted: April 19, 2022 at 2:25 am

Archaeologists and members of the Muwekma Ohlone Tribe worked together on the project, which revealed the longstanding genetic roots of the region's Native peoples. Courtesy of Far Western Anthropological Research Group

For decades, a misperception that the San Francisco Bay Areas Muwekma Ohlone Tribe was extinct barred its living members from receiving federal recognition.

Soon, however, that might change. As Celina Tebor reports for USA Today, a new DNA analysis shows a genetic through line between 2,000-year-old skeletons found in California and modern-day Muwekma Ohlone people.

The research, published in Proceedings of the National Academy of Sciences, flies in the face of more than a century of misconceptions about the tribe and its peoples long history.

The study reaffirms the Muwekma Ohlones deep-time ties to the area, providing evidence that disagrees with linguistic and archaeological reconstructions positing that the Ohlone are late migrants to the region, write the authors in the paper.

Members of the tribe, scholars and the public are hailing the work as a chance to correct the recordand perhaps open up opportunities for the tribe to regain federal recognition, which allows tribes to qualify for federal funds and grants and be acknowledged as independent and sovereign. In the early 20th century, the tribe was on a federal list of recognized tribes, but was removed in 1927.

The tribes history mirrors that of other Native Californians. After more than 10,000 years in the area, Native people were forced to submit to colonization and Christian indoctrinationfirst by the Spaniards, who arrived in 1776, and then, beginning in the 19th century, by settlers from the growing United States.

As a result, the Ohlone and other Native groups lost significant numbers to disease and forced labor. Before European contact, at least 300,000 Native people who spoke 135 distinct dialects lived in what is now California, per the Library of Congress. By 1848, that number had been halved. Just 25 years later, in 1873, only 30,000 remained. Now, USA Today reports, there are just 500 members of the Muwekma Ohlone Tribe.

The Ohlone people once lived on about 4.3 million acres in the Bay Area. But federal negligence and anthropologist A.L. Kroebers 1925 assessment that Native Californians were extinct for all practical purposes caused the federal government to first strip the Muwekma Ohlone of their land, then deny them federal recognition, writes Les W. Field, a cultural anthropologist who collaborates with the Muwekma Ohlone, in the Wicazo Sa Review.

Even though Kroeber recanted his erroneous statement in the 1950s, the lasting damage from his diagnosis meant the very much not-extinct members of the Muwekma Ohlone Tribe never regained federal recognition, according to the New York Times Sabrina Imbler.

The new research could change that. It arose after the 2014 selection of a site for a San Francisco Public Utilities Commission educational facility. The area likely contained human remains, triggering a California policy that requires developers to contact the most likely descendants of people buried in Native American sites before digging or building. When officials contacted the Muwekma Ohlone Tribe, its members requested a study of two settlement areasSi Tupentak (Place of the Water Round House Site) and Rummey Ta Kuuwi Tiprectak (Place of the Stream of the Lagoon Site).

Experts from Stanford University, the University of Illinois Urbana-Champaign, cultural resources consulting firm Far Western Anthropological Research Group and other institutions led the research.

But members of the Muwekma Ohlone Tribe were involved in every aspect of the study, from the initiative to pursue the project to the selection of research questions, in archaeological excavation and ancient genomics involving sites in their historical lands, and in present-day genomic analysis with current tribal members, according to the study. Tribal members even helped exhume the bodies.

Researchers and tribe members alike commented on the unique nature of the collaboration.

When youre a student doing the work, its not common to have this kind of direct connection to the people who are the data that youre working with, says lead author Alissa Severson, a doctoral student at Stanford University at the time of the research, in a statement. We got to have that dialogue, where we could discuss what were doing and what we found, and how that makes sense with their history. I felt very lucky to be working on this project. It felt like what we should be doing.

Jennifer A. Raff, a paleogeneticist at the University of Kansas who was not involved in the study, describes the work as fascinating.

If other tribes are interested in using genetics to investigate histories, they may be encouraged by the fact that some researchers are doing this work in a careful way, Raff tells Science magazines Andrew Curry.

The team analyzed the DNA of 12 individuals buried between 300 and 1,900 years ago, then compared the genomes to those of a variety of Indigenous Americans. They found genetic continuity between all 12 individuals studied and eight modern-day Muwekma Ohlone Tribe members.

It was surprising to find this level of continuity given the many disruptions the Ohlone people experienced during Spanish occupation, such as forced relocations and admixture with other tribes forcibly displaced by the Spanish, co-author Noah Rosenberg, a population geneticist at Stanford, tells the New York Times.

Tribe members hope the new evidence of the Muwekma Ohlone Tribes longstanding connection to the landand their ancestorswill spur politicians to finally recognize the tribe. According to an official tribal website, Muwekma Ohlone families started the reapplication process in the early 1980s and officially petitioned the U.S. government for recognition in 1995. Despite filing a lawsuit against the Bureau of Indian Affairs, the tribe is still not recognized by the U.S. government.

Co-author Alan Leventhal, a tribal ethnohistorian and archaeologist who works with the Muwekma Ohlone Tribe, tells USA Today hes hopeful this new research will help cut through some of the bureaucratic red tape thats been delaying the tribes petition.

Privately, this further validates the tribe, he says. Now, as politicians are reading, they're noticing. And now we'll be lending support for the tribe's reaffirmation.

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Expert explains causes of blindness in pets and ways to prevent it – The Indian Express

Posted: April 19, 2022 at 2:25 am

Just like human beings, pets can suffer from blindness, too, and only a few pet parents are aware of the causes, symptoms and prevention methods of blindness. Dr Dilip Sonune, the director of veterinary services at Wiggles.in says your pet may become blind due to several reasons, from poor nutrition to old age, injuries or even accidents.

Here are some common causes:

GlaucomaThis condition is caused by increased pressure in the eye. Glaucoma can occur due to genetics and sometimes other conditions like uveitis, eye tumor and lens luxation.

CataractThis condition causes painless cloudiness in the eye that can lead to partial or complete blindness. Uveitis in cats and factors like genetics and diabetes in dogs are common causes of cataract in pets.

Old ageLike humans, old age can cause blindness in pets, too.

Suddenly Acquired Retinal Degeneration Syndrome (SARDS)This is a condition in dogs that causes sudden blindness. It can occur in completely healthy dogs and the causes are unknown.

Progressive Retinal Atrophy (PRA)PRA is mostly an inherited disease that occurs commonly in dogs and rarely in cats.

Injury or traumaAn injury or trauma to the brain or the eye and eye area can also cause blindness.

Health conditions that can cause blindness in pets are diabetes, heart disease, kidney disease, liver disease and systemic diseases, says Dr Sonune.

Symptoms of blindness in pets

Early detection of symptoms can sometimes prevent complete blindness. If you notice any of the following in your pet, visit your veterinarian.

Afraid to move around. Bumping into furniture or other objects. Excessive anxiety/jumpy behaviour. Unable to find their food, water or toys. Puffy, cloudy, swollen, watery or red eyes. Irritation near the eye area. Hesitant and unwilling to explore new places. Depression

How can blindness be prevented in pets?

According to the doctor, here are some ways in which you can prevent blindness in pets:

1. Add foods to the diet that are good for their vision: Foods like broccoli, eggs (without yolk), fish, blueberries and carrots are great for your pets vision. Carrots especially, rich in beta carotene, make for an excellent food that maintains good vision. You can pick a few of the ingredients and blend them together with some water. Add the blend as a top-up to their food. Do check with your veterinarian before changing your pets diet.

2. Clean their eyes regularly: Use pet wipes, baby wipes or a small piece of wet cloth to clean their eyes on a regular basis. This maintains good eye hygiene and prevents infections.

3. Get the hair around the eyes trimmed: Sometimes, eye infections can be caused due to irritation caused by the hair around the eyes. Visit a professional grooming service to get it trimmed.

4. Do not let them put their head out of the car window: Many pet parents do this and although it can be fun, it can hurt them. Small pebbles or tiny insects can cause an injury; the dust can cause infections.

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Mississippi professor, engineer receives national award to help develop better vaccines, cancer treatments – Magnolia State Live – Magnolia State Live

Posted: April 19, 2022 at 2:24 am

Thomas Werfel, assistant professor of biomedical engineering at the University of Mississippi, has received a Faculty Early Career Development, or CAREER, award from the National Science Foundation.

The CAREER award, a five-year grant for $597,638, will fund Werfels efforts to create innovative biomaterials that will help human immune systems respond better to illnesses.

The immune system is one of the most complex systems in the body: molecules, cells and organs work together to keep a person healthy. It responds to all types of challenges such as infections, cancers and toxins with great precision in terms of timing and location.

Immunotherapies drugs that harness the power of the immune system are typically given all at once as single therapies. That means they often lack the level of precision needed in terms of where, how much and how long the drug is administered.

Werfels research seeks to radically improve the ability to program immune responses by developing biomaterials that can recruit, train and sustain relevant immune cells with greater accuracy.

Ultimately, this could result in vaccines and cancer treatments that maximize the effectiveness of the immune response.

We think our approach has great potential because it is based on the way the body naturally responds to infection, as opposed to traditional approaches to drug-making, said Werfel.

To achieve this, it is necessary to pursue new technologies that can perform in this novel manner. Im truly honored to receive the NSF CAREER award, as it allows me the time and resources to hopefully discover a way to improve health care for many Americans.

Werfel also has received anearly $800,000 grant from the American Cancer Societyin a complementary area: research into new treatments for metastatic breast cancer.

As part of his CAREER grant, Werfel plans to set up a Nanoengineering Research Experience for Undergraduates, with particular focus on underrepresented students from Mississippi and nearby. The summer program would provide research and professional development opportunities.

He also wants to establish a STEM Excursion program, where north Mississippi high school students can learn about nanobiotechnology from Ole Miss undergraduate researchers.

Werfel explained that these outreach efforts provide a great opportunity for students of all backgrounds to learn about this exciting new field. And, this gives our young academics the possibility to share their passion and gain mentoring skills.

The NSFs Faculty Early Career Development program supports early-career faculty who have the potential to serve as academic role models in research and education and to lead advances in the mission of their department or organization.

This prestigious award is designed to help early-career faculty build a firm foundation for a lifetime of leadership in integrating education and research.

Several UM researchers have received NSF CAREER Awards, but this is the first for the School of Engineering.

I am pleased that Thomas work has been recognized with this great honor, said Dave Puleo, dean of the School of Engineering. This is an excellent moment for the school and it demonstrates our efforts to give cutting-edge research opportunities to our students.

The project, titled Multimodal biomaterials for sequential delivery of diverse immunotherapeutic cargos, is jointly funded by the NSFs Biomaterials program and the Established Program to Stimulate Competitive Research. EPSCoR works to enhance the research competitiveness of certain jurisdictions, such as underfunded states, by strengthening STEM capacity and capability.

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Black Diamond Therapeutics Announces First Patient Dosed in Phase 1 Study of BDTX-1535, a MasterKey Inhibitor of EGFR for the Treatment of…

Posted: April 19, 2022 at 2:23 am

Clinical update expected in second half of 2023

CAMBRIDGE, Mass. and NEW YORK, April 18, 2022 (GLOBE NEWSWIRE) -- Black Diamond Therapeutics, Inc. (Nasdaq: BDTX), a precision oncology medicine company pioneering the discovery and development of MasterKey therapies, today announced the dosing of the first patient in the Phase 1 study evaluating BDTX-1535, a MasterKey inhibitor of epidermal growth factor receptor (EGFR) for the treatment of both non-small cell lung cancer (NSCLC) and glioblastoma (GBM)derived from Black Diamonds MAP discovery engine.

The dosing of the first patient in our Phase 1 study of BDTX-1535, a next generation brain-penetrant inhibitor of oncogenic EGFR MasterKey mutations is an important step as we believe this program is uniquely positioned to address the existing unmet needs of EGFR mutant NSCLC and GBM, said David M. Epstein, Ph.D., Chief Executive Officer of Black Diamond Therapeutics. This is the second MasterKey inhibitor derived from our MAP drug discovery engine; we are incredibly excited about BDTX-1535s advancement into the clinic and we look forward to providing a clinical update in the second half of 2023.

Despite recent successes in targeting EGFR-mutated NSCLC, there is still a need for better therapeutics for patients with disease progression following first-line EGFR inhibitors, said Melissa Johnson, MD, Director of Lung Cancer Research for Sarah Cannon Research Institute at Tennessee Oncology. We hope to assess the ability of BDTX-1535 to inhibit tumors with primary TKI-resistant EGFR mutations or those with on-target acquired resistance mutations.

NSCLC accounts for approximately 85% of lung cancer cases worldwide. About 10-20% of all lung cancer patients in North American and Europe, and up to 50% of those in Asia harbor mutations in EGFR. Intrinsic resistance EGFR mutations, of which G719X, S768I, L861Q are among the most frequent, account for 10-20% of EGFR mutations in NSCLC. The classical Exon19del and L858R mutations, which account for 80-90% of EGFR mutations in NSCLC, are well treated but resistance invariably emerges to current generation EGFR inhibitors.

"GBM is an aggressive form of brain cancer with limited treatment options, said Patrick Y. Wen, MD, Director, Center for Neuro-Oncology at Dana-Farber Cancer Institute. "A majority of GBM tumors will co-express EGFR alterations, including mutations, splice variants and amplification, making EGFR an attractive target for new therapies with CNS penetration and potency against the spectrum of co-expressed EGFR alterations.

Up to 50% of GBM tumors express one or more co-occurring oncogenic EGFR mutations that affect the extracellular region of the receptor tyrosine kinase, and consequently promote oncogenic activation. There are no precision oncology medicines approved to treat these patients. Black Diamond believes that current targeted therapies have been unsuccessful in treating GBM due to insufficiencies in (i) drug selectivity for EGFR GBM alterations versus EGFR wildtype, (ii) drug potency against the full spectrum of co-expressed EGFR alterations, and (iii) brain penetration.

About BDTX-1535BDTX-1535 is designed as an irreversible, mutant selective, brain-penetrant MasterKey inhibitor of oncogenic mutations of epidermal growth factor receptor (EGFR) expressed in glioblastoma multiforme (GBM) and intrinsic and acquired resistance EGFR mutations in non-small cell lung cancer (NSCLC). In pre-clinical studies, Black Diamond has demonstrated that oncogenic alterations of EGFR, particularly those associated with GBM, result in distinct conformations which impart unique pharmacology and drug resistance. It is estimated that approximately 50% of GBM patients harbor an oncogenic EGFR alteration that has the potential to be addressed by BDTX-1535, representing a potential patient population of greater than 60,000 patients annually across the US, EU, Japan and China. It is estimated that across the US, EU, Japan and China there are approximately 20,000 patients who are diagnosed annually with non-small cell lung cancer (NSCLC) harboring an EGFR intrinsic or acquired resistance mutation.

About Black DiamondBlack Diamond Therapeutics is a precision oncology medicine company pioneering the development of novel MasterKey therapies. Black Diamond is addressing the significant unmet need for novel precision oncology therapies for patients with genetically defined cancers who have limited treatment options. Black Diamond is built upon a deep understanding of cancer genetics, onco-protein function, and drug discovery. The Companys proprietary Mutation-Allostery-Pharmacology, or MAP drug discovery engine, is designed to allow Black Diamond to analyze population-level genetic sequencing tumor data to predict and validate oncogenic mutations that promote cancer across tumor types as MasterKey mutations. Black Diamond discovers and develops selective MasterKey therapies against these families of oncogenic mutations. Black Diamond was founded by David M. Epstein, Ph.D., and Elizabeth Buck, Ph.D. For more information, please visit http://www.blackdiamondtherapeutics.com.

Forward-Looking Statements

Statements contained in this press release regarding matters that are not historical facts are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. Because such statements are subject to risks and uncertainties, actual results may differ materially from those expressed or implied by such forward-looking statements. Such statements include, but are not limited to, statements regarding the Phase 1 study of BDTX-1535, including timing for future clinical updates, and the unmet need in patients with glioblastoma. Any forward-looking statements in this statement are based on managements current expectations of future events and are subject to a number of risks and uncertainties that could cause actual results to differ materially and adversely from those set forth in or implied by such forward-looking statements. Risks that contribute to the uncertain nature of the forward-looking statements include those risks and uncertainties set forth in the Companys 2021 annual report on Form 10-K filed with the United States Securities and Exchange Commission and its other filings filed with the United States Securities and Exchange Commission. All forward-looking statements contained in this press release speak only as of the date on which they were made. The Company undertakes no obligation to update such statements to reflect events that occur or circumstances that exist after the date on which they were made.

ContactsFor Investors:Julie Seidelinvestors@bdtx.com

For Media:Kathy Vincent(310) 403-8951media@bdtx.com

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Black Diamond Therapeutics Announces First Patient Dosed in Phase 1 Study of BDTX-1535, a MasterKey Inhibitor of EGFR for the Treatment of...

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ENHERTU Granted Priority Review in the U.S. for Patients with Previously Treated HER2 Mutant Metastatic Non-Small Cell Lung Cancer – Yahoo Finance

Posted: April 19, 2022 at 2:23 am

Based on pivotal DESTINY-Lung01 results showing Daiichi Sankyo and AstraZenecas ENHERTU demonstrated a 54.9% tumor response rate

If approved, ENHERTU to provide patients with a much-needed targeted therapy option

TOKYO & BASKING RIDGE, N.J., April 19, 2022--(BUSINESS WIRE)--Daiichi Sankyo (TSE: 4568) and AstraZeneca (LSE/STO/Nasdaq: AZN) have received notification of acceptance of the supplemental Biologics License Application (sBLA) of ENHERTU (fam-trastuzumab deruxtecan-nxki) for the treatment of adult patients in the U.S. with unresectable or metastatic non-small cell lung cancer (NSCLC) whose tumors have a HER2 (ERBB2) mutation and who have received a prior systemic therapy. The application has also been granted Priority Review.

ENHERTU is a HER2 directed antibody drug conjugate (ADC) being jointly developed by Daiichi Sankyo and AstraZeneca.

The U.S. Food and Drug Administration (FDA) grants Priority Review to applications for medicines that, if approved, would offer significant improvements over available options by demonstrating safety or efficacy improvements, preventing serious conditions or enhancing patient compliance. The Prescription Drug User Fee Act (PDUFA) date, the FDA action date for their regulatory decision, is during the third quarter of the 2022 calendar year. The Priority Review follows receipt of Breakthrough Therapy Designation, granted by the FDA in May 2020 for ENHERTU in this cancer type.

Lung cancer is the second most common form of cancer globally, with more than two million new cases diagnosed in 2020.1 For patients with metastatic NSCLC, prognosis is particularly poor, as only approximately 8% will live beyond five years after diagnosis.2 There are currently no HER2 directed therapies approved specifically for the treatment of HER2 mutant NSCLC, which occurs in approximately 2% to 4% of patients with non-squamous NSCLC.3,4

"The results of DESTINY-Lung-01 showed that ENHERTU is the first HER2 directed therapy to demonstrate a strong and robust tumor response in more than half of patients with previously treated HER2 mutant metastatic non-small cell lung cancer," said Ken Takeshita, MD, Global Head, R&D, Daiichi Sankyo. "Seeking approval in the U.S. for a third tumor type in three years further demonstrates the significant potential of ENHERTU in treating multiple HER2 targetable cancers."

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"The DESTINY-Lung01 trial confirmed the HER2 mutation as an actionable biomarker in non-small cell lung cancer," said Susan Galbraith, MBBChir, PhD, Executive Vice President, Oncology R&D, AstraZeneca. "If approved, ENHERTU has the potential to become a new standard treatment in this patient population, offering a much-needed option for patients with HER2 mutant metastatic non-small cell lung cancer who currently have no targeted treatment options."

The sBLA is based on data from the pivotal DESTINY-Lung01 phase 2 trial published in The New England Journal of Medicine, and is supported by the phase 1 trial (DS8201-A-J101) published in Cancer Discovery.

Primary results from the HER2 mutant cohort (cohort 2) of DESTINY-Lung01 in previously-treated HER2 mutant NSCLC demonstrated a confirmed objective response rate (ORR) of 54.9% (n=50; 95% confidence interval [CI]: 44.2-65.4) in patients treated with ENHERTU (6.4 mg/kg) as assessed by independent central review (ICR). Out of a total of 91 patients, one (1.1%) complete response (CR) and 49 (53.8%) partial responses (PR) were observed. A confirmed disease control rate (DCR) of 92.3% (95% CI: 84.8-96.9) was seen with a reduction in tumor size observed in most patients. After a median follow-up of 13.1 months, the median duration of response (DoR) for ENHERTU was 9.3 months (95% CI: 5.7-14.7). The median progression-free survival (PFS) was 8.2 months (95% CI: 6.0-11.9) and the median overall survival (OS) was 17.8 months (95% CI: 13.8-22.1).

The safety profile of the most common adverse events with ENHERTU in DESTINY-Lung01 was consistent with previous clinical trials. The most common grade 3 or higher drug-related treatment-emergent adverse events were neutropenia (18.7%), anemia (9.9%), nausea (8.8%), fatigue (6.6%), leukopenia (4.4%), diarrhea (3.3%) and vomiting (3.3%). Twenty-three patients (25%) discontinued treatment due to drug-related treatment-emergent adverse events. Overall, 26% of patients had interstitial lung disease (ILD) or pneumonitis related to treatment as determined by an independent adjudication committee. The majority of ILD events (75%) were low grade (grade 1 (12.5%) or grade 2 (62.5%)). Out of the total study population, four grade 3 (4.4%) and two grade 5 (2.2%) ILD or pneumonitis events were reported.

About DESTINY-Lung01 DESTINY-Lung01 is a global phase 2, open-label, two-cohort trial evaluating the efficacy and safety of ENHERTU in patients with HER2 mutant (6.4 mg/kg) or HER2 overexpressing (defined as IHC3+ or IHC2+) [6.4 mg/kg and 5.4 mg/kg] unresectable and/or metastatic non-squamous NSCLC who had progressed after one or more systemic therapies. The primary endpoint is confirmed ORR by ICR. Key secondary endpoints include DoR, DCR, PFS, OS and safety. DESTINY-Lung01 enrolled approximately 180 patients at multiple sites, including Asia, Europe and North America. For more information about the trial, visit ClinicalTrials.gov.

About HER2 Mutant NSCLC Lung cancer is the second most common form of cancer globally, with more than two million new cases diagnosed in 2020.1 In the U.S., lung cancer is the second most commonly diagnosed cancer, with more than 236,000 new cases expected in 2022.5 For patients with metastatic NSCLC, prognosis is particularly poor, as only approximately 8% will live beyond five years after diagnosis.2

HER2 is a tyrosine kinase receptor growth-promoting protein expressed on the surface of many types of tumors, including lung, breast, gastric and colorectal cancers. Certain HER2 gene alterations (called HER2 mutations) have been identified in NSCLC as distinct molecular targets and have been reported in approximately 2% to 4% of patients with non-squamous NSCLC.3,4 While HER2 gene mutations can occur in a range of patients, they are more commonly found in patients with NSCLC who are younger, female and have never smoked.6 HER2 gene mutations have been independently associated with cancer cell growth and poor prognosis, with an increased incidence of brain metastases.7 Although the role of anti-HER2 treatment is well established in breast and gastric cancers, HER2 is an emerging biomarker in NSCLC with no approved HER2 directed therapies.3,8 Next-generation sequencing has been utilized in the identification of HER2 (ERBB2) mutations.9

About ENHERTU ENHERTU (trastuzumab deruxtecan; fam-trastuzumab deruxtecan-nxki in the U.S. only) is a HER2 directed ADC. Designed using Daiichi Sankyos proprietary DXd ADC technology, ENHERTU is the lead ADC in the oncology portfolio of Daiichi Sankyo and the most advanced program in AstraZenecas ADC scientific platform. ENHERTU consists of a HER2 monoclonal antibody attached to a topoisomerase I inhibitor payload, an exatecan derivative, via a stable tetrapeptide-based cleavable linker.

ENHERTU (5.4 mg/kg) is approved in more than 40 countries for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received two or more prior anti-HER2-based regimens based on the results from the DESTINY-Breast01 trial.

ENHERTU (6.4 mg/kg) is approved in several countries for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a prior trastuzumab-based regimen based on the results from the DESTINY-Gastric01 trial.

ENHERTU is approved in the U.S. with Boxed WARNINGS for Interstitial Lung Disease and Embryo-Fetal Toxicity. For more information, please see the accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

About the ENHERTU Clinical Development Program A comprehensive global development program is underway evaluating the efficacy and safety of ENHERTU monotherapy across multiple HER2 targetable cancers including breast, gastric, lung and colorectal cancers. Trials in combination with other anticancer treatments, such as immunotherapy, are also underway.

Regulatory applications for ENHERTU are currently under review in Europe, Japan, U.S. and several other countries for the treatment of adult patients with unresectable or metastatic HER2 positive breast cancer who have received a prior anti-HER2-based regimen based on the results from the DESTINY-Breast03 trial.

ENHERTU also is currently under review in Europe for the treatment of adult patients with locally advanced or metastatic HER2 positive gastric or GEJ adenocarcinoma who have received a prior anti-HER2 based regimen based on the DESTINY-Gastric01 and DESTINY-Gastric02 trials.

About the Daiichi Sankyo and AstraZeneca Collaboration Daiichi Sankyo Company, Limited (referred to as Daiichi Sankyo) and AstraZeneca entered into a global collaboration to jointly develop and commercialize ENHERTU in March 2019 and datopotamab deruxtecan (Dato-DXd) in July 2020, except in Japan where Daiichi Sankyo maintains exclusive rights for each ADC. Daiichi Sankyo is responsible for the manufacturing and supply of ENHERTU and datopotamab deruxtecan.

U.S. Important Safety Information for ENHERTU

Indications ENHERTU is a HER2-directed antibody and topoisomerase inhibitor conjugate indicated for the treatment of adult patients with:

Unresectable or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting.

This indication is approved under accelerated approval based on tumor response rate and duration of response. Continued approval for this indication may be contingent upon verification and description of clinical benefit in a confirmatory trial.

WARNING: INTERSTITIAL LUNG DISEASE and EMBRYO-FETAL TOXICITY

Interstitial lung disease (ILD) and pneumonitis, including fatal cases, have been reported with ENHERTU. Monitor for and promptly investigate signs and symptoms including cough, dyspnea, fever, and other new or worsening respiratory symptoms. Permanently discontinue ENHERTU in all patients with Grade 2 or higher ILD/pneumonitis. Advise patients of the risk and to immediately report symptoms.

Exposure to ENHERTU during pregnancy can cause embryo-fetal harm. Advise patients of these risks and the need for effective contraception.

Contraindications None.

Warnings and Precautions Interstitial Lung Disease / Pneumonitis Severe, life-threatening, or fatal interstitial lung disease (ILD), including pneumonitis, can occur in patients treated with ENHERTU. Advise patients to immediately report cough, dyspnea, fever, and/or any new or worsening respiratory symptoms. Monitor patients for signs and symptoms of ILD. Promptly investigate evidence of ILD. Evaluate patients with suspected ILD by radiographic imaging. Consider consultation with a pulmonologist. For asymptomatic ILD/pneumonitis (Grade 1), interrupt ENHERTU until resolved to Grade 0, then if resolved in 28 days from date of onset, maintain dose. If resolved in >28 days from date of onset, reduce dose one level. Consider corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., 0.5 mg/kg/day prednisolone or equivalent). For symptomatic ILD/pneumonitis (Grade 2 or greater), permanently discontinue ENHERTU. Promptly initiate systemic corticosteroid treatment as soon as ILD/pneumonitis is suspected (e.g., 1 mg/kg/day prednisolone or equivalent) and continue for at least 14 days followed by gradual taper for at least 4 weeks.

Metastatic Breast Cancer In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, ILD occurred in 9% of patients. Fatal outcomes due to ILD and/or pneumonitis occurred in 2.6% of patients treated with ENHERTU. Median time to first onset was 4.1 months (range: 1.2 to 8.3).

Locally Advanced or Metastatic Gastric Cancer In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, ILD occurred in 10% of patients. Median time to first onset was 2.8 months (range: 1.2 to 21.0).

Neutropenia Severe neutropenia, including febrile neutropenia, can occur in patients treated with ENHERTU.Monitor complete blood counts prior to initiation of ENHERTU and prior to each dose, and as clinically indicated. For Grade 3 neutropenia (Absolute Neutrophil Count [ANC] <1.0 to 0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less, then maintain dose. For Grade 4 neutropenia (ANC <0.5 x 109/L) interrupt ENHERTU until resolved to Grade 2 or less. Reduce dose by one level. For febrile neutropenia (ANC <1.0 x 109/L and temperature >38.3C or a sustained temperature of 38C for more than 1 hour), interrupt ENHERTU until resolved. Reduce dose by one level.

Metastatic Breast Cancer In clinical studies, of the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU 5.4mg/kg, a decrease in neutrophil count was reported in 62% of patients. Sixteen percent had Grade 3 or 4 decrease in neutrophil count. Median time to first onset of decreased neutrophil count was 23 days (range: 6 to 547). Febrile neutropenia was reported in 1.7% of patients.

Locally Advanced or Metastatic Gastric Cancer In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, a decrease in neutrophil count was reported in 72% of patients. Fifty-one percent had Grade 3 or 4 decreased neutrophil count. Median time to first onset of decreased neutrophil count was 16 days (range: 4 to 187). Febrile neutropenia was reported in 4.8% of patients.

Left Ventricular Dysfunction Patients treated with ENHERTU may be at increased risk of developing left ventricular dysfunction. Left ventricular ejection fraction (LVEF) decrease has been observed with anti-HER2 therapies, including ENHERTU. In the 234 patients with unresectable or metastatic HER2-positive breast cancer who received ENHERTU, two cases (0.9%) of asymptomatic LVEF decrease were reported. In DESTINY-Gastric01, of the 125 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg, no clinical adverse events of heart failure were reported; however, on echocardiography, 8% were found to have asymptomatic Grade 2 decrease in LVEF. Treatment with ENHERTU has not been studied in patients with a history of clinically significant cardiac disease or LVEF <50% prior to initiation of treatment.

Assess LVEF prior to initiation of ENHERTU and at regular intervals during treatment as clinically indicated. When LVEF is >45% and absolute decrease from baseline is 10-20%, continue treatment with ENHERTU. When LVEF is 40-45% and absolute decrease from baseline is <10%, continue treatment with ENHERTU and repeat LVEF assessment within 3 weeks. When LVEF is 40-45% and absolute decrease from baseline is 10-20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF has not recovered to within 10% from baseline, permanently discontinue ENHERTU. If LVEF recovers to within 10% from baseline, resume treatment with ENHERTU at the same dose. When LVEF is <40% or absolute decrease from baseline is >20%, interrupt ENHERTU and repeat LVEF assessment within 3 weeks. If LVEF of <40% or absolute decrease from baseline of >20% is confirmed, permanently discontinue ENHERTU. Permanently discontinue ENHERTU in patients with symptomatic congestive heart failure.

Embryo-Fetal Toxicity ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. Verify the pregnancy status of females of reproductive potential prior to the initiation of ENHERTU. Advise females of reproductive potential to use effective contraception during treatment and for at least 7 months following the last dose of ENHERTU. Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months after the last dose of ENHERTU.

Additional Dose Modifications Thrombocytopenia For Grade 3 thrombocytopenia (platelets <50 to 25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less, then maintain dose. For Grade 4 thrombocytopenia (platelets <25 x 109/L) interrupt ENHERTU until resolved to Grade 1 or less. Reduce dose by one level.

Adverse Reactions Metastatic Breast Cancer The safety of ENHERTU was evaluated in a pooled analysis of 234 patients with unresectable or metastatic HER2-positive breast cancer who received at least one dose of ENHERTU 5.4 mg/kg in DESTINY-Breast01 and Study DS8201-A-J101. ENHERTU was administered by intravenous infusion once every three weeks. The median duration of treatment was 7 months (range: 0.7 to 31).

Serious adverse reactions occurred in 20% of patients receiving ENHERTU. Serious adverse reactions in >1% of patients who received ENHERTU were interstitial lung disease, pneumonia, vomiting, nausea, cellulitis, hypokalemia, and intestinal obstruction. Fatalities due to adverse reactions occurred in 4.3% of patients including interstitial lung disease (2.6%), and the following events occurred in one patient each (0.4%): acute hepatic failure/acute kidney injury, general physical health deterioration, pneumonia, and hemorrhagic shock.

ENHERTU was permanently discontinued in 9% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 33% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, thrombocytopenia, leukopenia, upper respiratory tract infection, fatigue, nausea, and ILD. Dose reductions occurred in 18% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were fatigue, nausea, and neutropenia.

The most common (20%) adverse reactions, including laboratory abnormalities, were nausea (79%), white blood cell count decreased (70%), hemoglobin decreased (70%), neutrophil count decreased (62%), fatigue (59%), vomiting (47%), alopecia (46%), aspartate aminotransferase increased (41%), alanine aminotransferase increased (38%), platelet count decreased (37%), constipation (35%), decreased appetite (32%), anemia (31%), diarrhea (29%), hypokalemia (26%), and cough (20%).

Locally Advanced or Metastatic Gastric Cancer The safety of ENHERTU was evaluated in 187 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma in DESTINY-Gastric01. Patients intravenously received at least one dose of either ENHERTU (N=125) 6.4 mg/kg once every three weeks or either irinotecan (N=55) 150 mg/m2 biweekly or paclitaxel (N=7) 80 mg/m2 weekly for 3 weeks. The median duration of treatment was 4.6 months (range: 0.7 to 22.3) in the ENHERTU group and 2.8 months (range: 0.5 to 13.1) in the irinotecan/paclitaxel group.

Serious adverse reactions occurred in 44% of patients receiving ENHERTU 6.4 mg/kg. Serious adverse reactions in >2% of patients who received ENHERTU were decreased appetite, ILD, anemia, dehydration, pneumonia, cholestatic jaundice, pyrexia, and tumor hemorrhage. Fatalities due to adverse reactions occurred in 2.4% of patients: disseminated intravascular coagulation, large intestine perforation, and pneumonia occurred in one patient each (0.8%).

ENHERTU was permanently discontinued in 15% of patients, of which ILD accounted for 6%. Dose interruptions due to adverse reactions occurred in 62% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose interruption were neutropenia, anemia, decreased appetite, leukopenia, fatigue, thrombocytopenia, ILD, pneumonia, lymphopenia, upper respiratory tract infection, diarrhea, and hypokalemia. Dose reductions occurred in 32% of patients treated with ENHERTU. The most frequent adverse reactions (>2%) associated with dose reduction were neutropenia, decreased appetite, fatigue, nausea, and febrile neutropenia.

The most common (20%) adverse reactions, including laboratory abnormalities, were hemoglobin decreased (75%), white blood cell count decreased (74%), neutrophil count decreased (72%), lymphocyte count decreased (70%), platelet count decreased (68%), nausea (63%), decreased appetite (60%), anemia (58%), aspartate aminotransferase increased (58%), fatigue (55%), blood alkaline phosphatase increased (54%), alanine aminotransferase increased (47%), diarrhea (32%), hypokalemia (30%), vomiting (26%), constipation (24%), blood bilirubin increased (24%), pyrexia (24%), and alopecia (22%).

Use in Specific Populations

Pregnancy: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise patients of the potential risks to a fetus. There are clinical considerations if ENHERTU is used in pregnant women, or if a patient becomes pregnant within 7 months following the last dose of ENHERTU.

Lactation: There are no data regarding the presence of ENHERTU in human milk, the effects on the breastfed child, or the effects on milk production. Because of the potential for serious adverse reactions in a breastfed child, advise women not to breastfeed during treatment with ENHERTU and for 7 months after the last dose.

Females and Males of Reproductive Potential: Pregnancy testing: Verify pregnancy status of females of reproductive potential prior to initiation of ENHERTU. Contraception: Females: ENHERTU can cause fetal harm when administered to a pregnant woman. Advise females of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 7 months following the last dose. Males: Advise male patients with female partners of reproductive potential to use effective contraception during treatment with ENHERTU and for at least 4 months following the last dose. Infertility: ENHERTU may impair male reproductive function and fertility.

Pediatric Use: Safety and effectiveness of ENHERTU have not been established in pediatric patients.

Geriatric Use: Of the 234 patients with HER2-positive breast cancer treated with ENHERTU 5.4 mg/kg, 26% were 65 years and 5% were 75 years. No overall differences in efficacy were observed between patients 65 years of age compared to younger patients. There was a higher incidence of Grade 3-4 adverse reactions observed in patients aged 65 years (53%) as compared to younger patients (42%). Of the 125 patients with locally advanced or metastatic HER2-positive gastric or GEJ adenocarcinoma treated with ENHERTU 6.4 mg/kg in DESTINY-Gastric01, 56% were 65 years and 14% were 75 years. No overall differences in efficacy or safety were observed between patients 65 years of age compared to younger patients.

Hepatic Impairment: In patients with moderate hepatic impairment, due to potentially increased exposure, closely monitor for increased toxicities related to the topoisomerase inhibitor.

To report SUSPECTED ADVERSE REACTIONS, contact Daiichi Sankyo, Inc. at 1-877-437-7763 or FDA at 1-800-FDA-1088 or fda.gov/medwatch.

Please see accompanying full Prescribing Information, including Boxed WARNINGS, and Medication Guide.

About Daiichi Sankyo Daiichi Sankyo is dedicated to creating new modalities and innovative medicines by leveraging our world-class science and technology for our purpose "to contribute to the enrichment of quality of life around the world." In addition to our current portfolio of medicines for cancer and cardiovascular disease, Daiichi Sankyo is primarily focused on developing novel therapies for people with cancer as well as other diseases with high unmet medical needs. With more than 100 years of scientific expertise and a presence in more than 20 countries, Daiichi Sankyo and its 16,000 employees around the world draw upon a rich legacy of innovation to realize our 2030 Vision to become an "Innovative Global Healthcare Company Contributing to the Sustainable Development of Society." For more information, please visit http://www.daiichisankyo.com.

References1 WHO. Cancer Today. 2020. Accessed April 2022. 2 America Cancer Society. Lung Cancer Survival Rates. Accessed April 2022. 3 Liu S, et al. Clin Cancer Res. 2018;24(11):2594-2604. 4 Campbell JD, et al. Nat Genet. 2016 Jun;48(6):607-16. 5 American Cancer Society. Key Statistics for Lung Cancer. Accessed April 2022. 6 Pillai RN, et al. Cancer. 2017;123:4099-105. 7 Offin M, et al. Cancer. 2019;125:4380-7. 8 Zhou J, et al. Ther Adv Med Oncol. 2020;12. 9 Hechtman, J, et al. Cancer Cyto. 2019; 127 (7): 428-431.

View source version on businesswire.com: https://www.businesswire.com/news/home/20220418005432/en/

Contacts

Media Contacts:Global: Victoria AmariDaiichi Sankyo, Inc.vamari@dsi.com +1 908 900 3010 (mobile)

US: Don MurphyDaiichi Sankyo, Inc.domurphy@dsi.com +1 917 817 2649 (mobile)

EU: Lydia WormsDaiichi Sankyo Europe GmbHlydia.worms@daiichi-sankyo.eu +49 (89) 7808751 (office)+49 176 11780861 (mobile)

Japan: Masashi KawaseDaiichi Sankyo Co., Ltd.kawase.masashi.a2@daiichisankyo.co.jp +81 3 6225 1126 (office)

Investor Relations Contact: DaiichiSankyoIR@daiichisankyo.co.jp

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ENHERTU Granted Priority Review in the U.S. for Patients with Previously Treated HER2 Mutant Metastatic Non-Small Cell Lung Cancer - Yahoo Finance

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Tumors Change Their Metabolism to Spread More Effectively – Weill Cornell Medicine Newsroom

Posted: April 19, 2022 at 2:23 am

Cancer cells can disrupt a metabolic pathway that breaks down fats and proteins to boost the levels of a byproduct called methylmalonic acid, thereby driving metastasis, according to research led by scientists at Weill Cornell Medicine. The findings open a new lead for understanding how tumors metastasize, or spread to other tissues, and hints at novel ways to block the spread of cancer by targeting the process.

The new results, published March 31 in Nature Metabolism, show that metastatic tumors suppress the activity of a key enzyme in propionate metabolism, the process by which cells digest certain fatty acids and protein components. Suppressing the enzyme increases production of methylmalonic acid (MMA). That, in turn, causes the cells to become more aggressive and invasive.

Cancer is the second leading cause of death worldwide, and metastasis drives much of that mortality. Once a tumor begins to metastasize to different tissues and organs around the body, it can quickly become difficult or impossible to treat. However, researchers have made few inroads in understanding how a tumor cell acquires the ability to metastasize.

A lot of work has been focused on primary tumor initiation and growth, or examining the metastatic tumor, but to go from the primary tumor to the metastatic tumor, that transition has not been studied very extensively, said co-senior author Dr. John Blenis, the Anna-Maria and Stephen Kellen Professor in Cancer Research, professor of pharmacology and associate director of basic science of the Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine.

To address that gap, Dr. Blenis and his colleagues have worked for several years to characterize the metabolic changes that cells undergo during the metastatic transition. That effort previously revealed that as people age, their bodies produce more serum MMA (although the source remains unknown), and that higher MMA levels drive worse cancer outcomes. Healthy cells also produce MMA, though, so in the new study Dr. Bleniss team probed the metabolites cancer-related activities more deeply.

Cancer cells themselves can hijack the pathway that makes methylmalonic acid and this forms a feed-forward cycle that drives cancer progression towards more aggressive and more metastatic forms, said co-first author Dr. Vivien Low, a postdoctoral fellow in Dr. Bleniss lab. The other co-first authors Dr. Ana Gomes and Dr. Didem Ilter, were also postdoctoral fellows in the lab at the time of the study. Dr. Gomes is now a faculty member and Dr. Ilter is a research scientist at H. Lee Moffitt Cancer Center & Research Institute.

The discovery adds to a growing body of work showing that specific products of metabolism, called oncometabolites, can drive many aspects of cancer progression and metastasis.

While the new paper focused on various models of breast cancer, Dr. Low said the team is now analyzing other types of cancer cells as well, where they expect to find similar mechanisms operating. The scientists are also searching for ways to attack the process.

Metastasis is responsible for about 80 to 90 percent of cancer-related mortality, so if we can predict when someone has the potential to develop metastatic tumors, or treat those metastatic tumors that might have this pathway up-regulated, then we might have a very effective, novel therapy, Dr. Blenis said.

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Tumors Change Their Metabolism to Spread More Effectively - Weill Cornell Medicine Newsroom

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Oncolytics Biotech Announces Publication of Preclinical Data Demonstrating the Synergistic Anti-Cancer Activity of Pelareorep Combined with CAR T Cell…

Posted: April 19, 2022 at 2:23 am

- Pelareorep-CAR T combination may expand the commercial potential of CAR T cells to solid tumors

- Combining CAR T cells with pelareorep prevented antigen escape by creating CAR T cells with dual specificity through a novel mechanism

-Loading CAR T cells with pelareorep led to dramatic improvements in their persistence and anti-cancer activity as well as cures in multiple murine solid tumor models

SAN DIEGO, Calif. and CALGARY, AB, April 14, 2022 /PRNewswire/ --Oncolytics BiotechInc. (NASDAQ: ONCY) (TSX: ONC) today announced the publication of preclinical data demonstrating the synergistic anti-cancer activity of pelareorep combined with chimeric antigen receptor (CAR) T cell therapy in solid tumors. The paper, entitled "Oncolytic virus-mediated expansion of dual-specific CAR T cells improves efficacy against solid tumors in mice," was published in Science Translational Medicine in collaboration with researchers at several prestigious institutions, including the Mayo Clinic and Duke University. A link to the paper can be found by clicking here.

"Having these results published in such a high-impact journal provides important external validation of their significance," said Thomas Heineman, M.D., Ph.D., Chief Medical Officer of Oncolytics Biotech Inc. "While CAR T cells have generated long-term cures in hematologic malignancies1, the immunosuppressive tumor microenvironments (TMEs) of solid organ cancers have thus far limited their efficacy in these indications. Pelareorep has repeatedly been shown to reverse immunosuppressive TMEs, and in the present publication pelareorep is shown to enable the effectiveness of CAR T cells in multiple murine solid tumor models. This is a powerful finding that, if translated to the clinic, could significantly improve the prognosis of patients with a variety of highly prevalent cancers by providing a novel and potentially durable treatment option. By demonstrating the ability to improve T cell perseverance, reduce antigen escape, and overcome challenging solid tumor TMEs, the inclusion of pelareorep addresses the three most challenging roadblocks to effective CAR T therapy."

Andrew de Guttadauro, President of Oncolytics Biotech U.S. and Global Head of Business Development, added, "Despite revolutionizing the treatment of certain cancers and surpassing a billion dollars in sales last year, CAR T therapies currently only serve a small subset of patients suffering from hematologic malignancies. With these latest results, we now have strong preclinical evidence that pelareorep can fully unlock the value of CAR T therapies by expanding their commercial potential to the significantly larger market of cancer patients who are battling solid tumors."

Preclinical studies published in the paper evaluated the persistence and efficacy of pelareorep-loaded CAR T cells ("CAR/Pela therapy") in multiple murine solid tumor models. The effects of combining CAR/Pela therapy with a subsequent intravenous dose of pelareorep ("pelareorep boost") were also investigated. Key data and conclusions from the paper include:

Dr. Matt Coffey, President and Chief Executive Officer of Oncolytics Biotech Inc. and co-author of the paper commented, "These exciting results are an excellent example of how we are leveraging collaborations with key opinion leaders and premier research institutions to broaden pelareorep's potential therapeutic impact. This allows us to remain primarily focused on our lead breast cancer program, which has shown how pelareorep's ability to promote tumor T cell infiltration leads to synergy with checkpoint inhibitors in the clinic. These newly published preclinical findings show pelareorep's synergistic benefits extend even beyond checkpoint inhibitors and highlight an opportunity to increase our addressable patient population. As we pursue this opportunity moving forward, we intend to utilize relationships with academic or industry partners so that we can continue to execute on our clinical and corporate objectives with efficiency."

About CAR T cells and CAR T therapy

TheCAR T process begins when blood is drawn from a patient and their T cells are separated so they can be genetically engineered to produce chimeric antigen receptors (CARs). These receptors enable the T cells to recognize and attach to a specific protein or antigen on tumor cells. Once the engineering process is complete, a laboratory can increase the number of CAR T cells into the hundreds of millions. Finally, the CAR T cells will be infused back into the patient where, ideally, the engineered cells further multiply and recognize and kill cancer cells. Historically, solid tumors have been considered beyond the reach of CAR T therapy due to their tumor microenvironment, which is detrimental to CAR T cell entry and activity, amongst other challenges.2

About Science Translational Medicine

Science Translational Medicineis the leading weekly online journal publishing translational research at the intersection of science, engineering, and medicine. The goal of Science Translational Medicine is to promote human health by providing a forum for communicating the latest research advances from biomedical, translational, and clinical researchers from all established and emerging disciplines relevant to medicine. In addition to original research, Science Translational Medicine also publishes Reviews, Editorials, Focus articles, and Viewpoints.

About Oncolytics Biotech Inc.

Oncolytics is a biotechnology company developing pelareorep, an intravenously delivered immunotherapeutic agent. This compound induces anti-cancer immune responses and promotes an inflamed tumor phenotype -- turning "cold" tumors "hot" -- through innate and adaptive immune responses to treat a variety of cancers.

Pelareorep has demonstrated synergies with immune checkpoint inhibitors and may also be synergistic with other approved oncology treatments. Oncolytics is currently conducting and planning clinical trials evaluating pelareorep in combination with checkpoint inhibitors and targeted therapies in solid and hematological malignancies as it advances towards a registration study in metastatic breast cancer. For further information, please visit:www.oncolyticsbiotech.com.

References

1. Melenhorst, J.J., Chen, G.M., Wang, M.et al.Decade-long leukaemia remissions with persistence of CD4+CAR T cells.Nature(2022). https://doi.org/10.1038/s41586-021-04390-6

2. National Cancer Institute. CAR T Cells: Engineering Patients' Immune Cells to Treat Their Cancers. Updated July 31, 2019. Accessed February 18, 2021.https://www.cancer.gov/about-cancer/treatment/research/car-t-cells

This press release contains forward-looking statements, within the meaning of Section 21E of the Securities Exchange Act of 1934, as amended and forward-looking information under applicable Canadian securities laws (such forward-looking statements and forward-looking information are collectively referred to herein as "forward-looking statements"). Forward-looking statements contained in this press release include statements regarding Oncolytics' belief as to the potential and benefits of pelareorep as a cancer therapeutic; Oncolytics' expectations as to the purpose, design, outcomes and benefits of its current or pending clinical trials involving pelareorep; including potentially significantly improving the prognosis of patients with a variety of highly-prevalent cancers by providing them with a novel and potentially durable treatment option and the opportunity to potentially expand our addressable patient population; our intention to utilize relationships with academic or industry partners so that we can continue to execute on our clinical and corporate objectives with efficiency; our leveraging of collaborations with key opinion leaders to broaden pelareorep's potential therapeutic impact; our plans to advance towards a registration study in metastatic breast cancer; and other statements related to anticipated developments in Oncolytics' business and technologies. In any forward-looking statement in which Oncolytics expresses an expectation or belief as to future results, such expectations or beliefs are expressed in good faith and are believed to have a reasonable basis, but there can be no assurance that the statement or expectation or belief will be achieved. Such forward-looking statements involve known and unknown risks and uncertainties, which could cause Oncolytics' actual results to differ materially from those in the forward-looking statements. Such risks and uncertainties include, among others, the availability of funds and resources to pursue research and development projects, the efficacy of pelareorep as a cancer treatment, the success and timely completion of clinical studies and trials, Oncolytics' ability to successfully commercialize pelareorep, uncertainties related to the research and development of pharmaceuticals, uncertainties related to the regulatory process and general changes to the economic environment. In particular, we may be impacted by business interruptions resulting from COVID-19 coronavirus, including operating, manufacturing supply chain, clinical trial and project development delays and disruptions, labour shortages, travel and shipping disruption, and shutdowns (including as a result of government regulation and prevention measures). It is unknown whether and how Oncolytics may be affected if the COVID-19 pandemic persists for an extended period of time. We may incur expenses or delays relating to such events outside of our control, which could have a material adverse impact on our business, operating results and financial condition.Investors should consult Oncolytics' quarterly and annual filings with the Canadian and U.S. securities commissions for additional information on risks and uncertainties relating to the forward-looking statements. Investors are cautioned against placing undue reliance on forward-looking statements. The Company does not undertake any obligation to update these forward-looking statements, except as required by applicable laws.

Company Contact

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Director of IR & Communication

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Investor Relations for Oncolytics

Timothy McCarthy

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SOURCE Oncolytics Biotech Inc.

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Oncolytics Biotech Announces Publication of Preclinical Data Demonstrating the Synergistic Anti-Cancer Activity of Pelareorep Combined with CAR T Cell...

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