Tokyo This month, a team of researchers at Osaka University declared an experimental treatment involving four patients suffering from corneal disease a success. The patients, who ranged in age from their 30s to 70s, received transplanted stem cells grown in the lab, known as iPS cells. Three had improved sight, and all were free of side effects one year later.

"This could be a revolutionary treatment that could overcome the challenges that existing treatment has faced, such as a shortage of cornea donors or transplant rejection," Koji Nishida, an Osaka University professor of ophthalmology, said at a news conference.

It was the latest in a flurry of iPS-related announcements in Japan as the country tries to carve a niche in "regenerative medicine" by culturing healthy cells to replace diseased, injured or non-functioning ones.

Induced pluripotent stem (iPS) cells are altered to revert to a non-differentiated "stem" state the building blocks of most organs. The stem cells can then be used to repair human tissues or grow organs.

Japan has invested $970 million in regenerative medicine, focusing on iPS as a strategy for coping with the world's oldest population and as a source of future economic growth. iPS is particularly attractive for Japan, which has one of the lowest rates of organ donation in the industrialized world.

iPS stem cell research in Japan took off after 2012, when biologist Shinya Yamanaka received the Nobel Prize in physiology or medicine after he discovered how to transform mature skin or blood cells into immature stem cells, which can then become neurons, muscle, cartilage or heart muscle cells.

Yamanaka went into medicine after his own father contracted hepatitis C a disease that became treatable 20 years later. Had iPS cells been available as a testing medium, he said, that treatment could have been developed much faster.

In the time since, numerous small-scale trials have been conducted for diseases like age-related macular degeneration, Parkinson's disease and arthritic disorders. In 2020, a six-day-old infant with a liver disorder received an iPS treatment that enabled the child to survive until it was old enough for a liver transplant. A stem cell transplant treatment was approved in 2019 for spinal-cord injuries in Japan.

iPS also offers hope for treating intractable and rare diseases like ALS - or Lou Gehrig's disease - and Alzheimer's.

And Yamanaka's findings offer a solution to the politically divisive dilemma posed by the use of embryonic stem cells, which rely on fertilized human eggs.

The development also eliminates the risk of transplant rejection of donor stem cells, since infinite lines of stem cells can be grown in a lab from as little as about two teaspoons of a patient's own skin or blood cells.

To reduce the massive cost and time needed to create iPS cells from each patient, a donor bank stockpile was set up in conjunction with the Red Cross that identified a tiny population of "super donors" whose blood can be used for many immunological types.

The corneal patients in the Osaka University trial received donor-generated iPS cells.

"I couldn't say Japan is leading the way with iPS because everybody, everybody's using it," David Cyranoski, a science policy researcher at Kyoto University's Institute for the Advanced Study of Human Biology, told CBS News. "It's such a powerful technology and it's so easy to adapt."

But while treatments using iPS offer hope for the future, approval is years away. "Stem cells themselves are harder to use than people thought," Cyranoski said, adding the therapies "haven't really proven themselves yet."

Despite hundreds of clinics in the United States offering unproven stem-cell therapies, which have been implicated in scores of deaths and injuries, the FDA has approved only blood stem cell transplantations for cancers and disorders of the blood and immune systems.

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To help cope with the world's oldest population, Japan is investing in transplanted iPS stem cells - CBS News

Stem cell transplants can effectively cure a wide range of diseases, from blood cancers to rare genetic disorders. They've been used for decades and are considered standard treatment for certain conditions.

But for a good number of patients, stem cell transplants are out of reach. Drug regimens used to prepare the body for a transplant are toxic and can cause serious side effects. The transplanted cells don't always "engraft," or take root in the bone marrow. Even when they do, patients' disease may linger or recur.

A biotech startup launching Wednesday with $50 million in funding hopes that, by combining cell, antibody and gene editing technologies, at least some of these problems can be overcome. Called Cimeio Therapeutics, the new company is led by a team of pharmaceutical industry veterans and an advisory board filled with scientific luminaries, including immunologist Jeffrey Bluestone and gene editing pioneer Fyodor Urnov.

Cimeio's approach involves "shielding" transplanted cells by genetically editing them in ways that allows paired immunotherapies to be safely used both before and after a transplant.

Thomas Fuchs

Courtesy of Cimeio Therapeutics

"We think that this can really unleash the power of hematopoietic stem cell transplant and make a lot more patients eligible for it," said Thomas Fuchs, Cimeio's CEO and a former Genentech executive.

The "shielding" technology used by Cimeio was developed in Switzerland at the laboratory of Lukas Jeker, a physician-scientist from Basel University Hospital who will join Cimeio as head of gene editing.

Jeker's lab discovered that protein receptors on the surface of cells could be genetically edited in such a way that prevented antibodies from binding to them, while leaving their function intact. In preclinical testing, these edits could cloak, or "shield," the cells from being depleted by antibody drugs and T cell therapies.

The work could have powerful implications for improving stem cell transplant and adoptive cell therapy, according to Fuchs.

Once a stem cell or T cell is shielded, a complementary immunotherapy could be used to either help ready patients for a transplant or to further treat disease afterwards, he said. "Maybe you could give a cycle or two of the paired immunotherapy, implant the shielded cells and then continue to administer the immunotherapy," he added.

If the shielding works as intended, Cimeio could develop treatments for conditioning that are more tolerable than the chemotherapy or radiation-based regimens currently in use. Shielding might also allow existing drugs that target cell proteins on healthy as well as diseased cells to be used more flexibly with transplants, such as to treat residual disease that lingers afterwards.

For example, Cimeio could engineer stem cells that are protected against binding via a protein called CD19 that's often the target for CAR-T therapies that treat lymphoma, but is also found on healthy B cells that help the immune system fight off threats.

"One benefit could be that you could prevent a lifetime of B cell depletion, which happens when you give a CAR-T," said Fuchs.

Alex Mayweg

Courtesy of Cimeio Therapeutics

Cimeio was built from Jeker's lab by Versant Ventures at the company's "Ridgeline" incubator in Basel, which has previously produced companies like Monte Rosa Therapeutics and Black Diamond Therapeutics. The initial $50 million Versant provided will fund Cimeio through next year, said Alex Mayweg, a managing director at the venture firm and a Cimeio board member. Additional investors will be brought on later this year or early next, Mayweg said.

Cimeio will need the money, as its research and development plans are expansive. The company has identified four drug candidates already and envisions a dozen more behind those, said Fuchs. Its research spans blood cancers, rare genetic diseases and autoimmune disorders.

In some cases, Cimeio will develop paired immunotherapies to go with the shielded cells. In others, it will use existing treatments. Three of the first four candidates involve protecting hematopoietic stem cells, while the fourth involves T cells. The company hopes to begin human testing next year.

Cimeio plans to choose gene editing technologies based on the type of alteration it needs to make to shield cells. "Rather than building up an internal editing capability," Mayweg said, "we wanted to stay as flexible as possible."

That might mean partnerships or alliances with other companies, some of which have reached out to Cimeio already, according to Mayweg.

Cimeio is aided by a group of scientific advisers notable for their work in areas the company is focusing on. Urnov, of the University of California, Berkeley, is well known for his research in gene editing using zinc finger nucleases and CRISPR. Bluestone previously led the Parker Institute for Cancer Immunotherapy and is CEO of the cell therapy-focused biotech Sonoma Biotherapeutics.

Suneet Agarwal, a co-program leader of the stem cell transplant center at Boston Children's Cancer and Blood Disorders Center, is also on the advisory board, while Cimeio has a research collaboration in place with Matthew Porteus, a gene editing specialist at Stanford University.

About 20 people currently work at Cimeio directly, a number Fuchs expects will grow as the company's research advances. Another 15 are currently supporting Cimeio from Versant's Ridgeline group.

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The introduction of CAR engineering to adoptive cell therapy has led to immune effector cell treatments with improved cytotoxicity.

In hematologic oncology, advancements in chimeric antigen receptors (CARs) for T-cell therapy have led to new investigations and an emerging role for CAR-natural killer (NK) cell therapy. Here we review why CAR-NK cell therapy is an area of interest, how it differentiates from CAR T-cell therapy, its potential challenges, and the current stage of development of this form of treatment.

The introduction of CAR engineering to adoptive cell therapy has led to immune effector cell treatments with improved cytotoxicity. This has been a major advancement in treatment for many patients with relapsed or refractory hematologic malignancies.1

Autologous CAR T cells were used in pioneering therapies, and their efficacy has led to FDA approvals in hematologic malignancies.1 For example, tisagenlecleucel (Kymriah), a CAR T-cell therapy, was approved for patients with relapsed/refractory acute lymphoblastic leukemia based on trial results showing an overall response rate of 81%, with 60% of patients achieving complete remission.2,3

However, despite their clinical efficacy, CAR T cells have limitations.4 Not all patients are candidates for CAR T-cell therapy. For example, heavily pretreated patients may not have sufficient autologous T cells to achieve clinically relevant doses of CAR T cells.1,4 Also, generating individualized autologous CAR T-cell products for each patient can take weeks, which can lead to unacceptable treatment delays in patients with rapidly progressive disease. Furthermore, patients receiving CAR T cells are at risk of developing graft-vs-host disease (GVHD) even if human leukocyte antigen (HLA) matching between donor and recipient is performed.

This form of therapy has also yet to make significant headway in treating patients with solid tumors. Few patients with solid malignancies have achieved complete responses to date, potentially due to limited expansion or persistence of CAR T cells and the inability of these cells to penetrate solid tumors.5

Moreover, long-term persistence of CAR T cells may cause cytokine release syndrome (CRS) and immune effector cellassociated neurotoxicity syndrome (ICANS), which can be life threatening.1,4,6 Lastly, target antigen loss after therapy can render CAR T immune cells ineffective due to their dependence on antigens for efficacy.

However, interest in CAR NK-cell therapy has resulted in ongoing research.1,7

Peter Riedell, MD, assistant professor of medicine, Section of Hematology/Oncology, University of Chicago Medicine, provided his insights in an interview with Targeted Therapies in OncologyTM.

CAR T-cell therapies take time, and this can be problematic for patients [who] have more rapidly progressive disease and need therapy urgently, said Riedell in an interview comparing CAR T-cell therapy to CAR-NK cell therapy. Having a cellular therapy product which is off-the-shelf is very attractive as it means we may be able to treat patients sooner rather than later with this therapy, he added.

NK cells, which were discovered almost 50 years ago, can defend against tumors in most tissues without requiring detection of specific tumor antigens.7 Potent innate anti-tumor activity and favorable safety profile features have promoted interest in CAR-NK cell immunotherapy.

NK toxicity against tumor cells involves both innate and adaptive immunity.7,8 For example, unlike T cells, NK cells can kill tumor cells without expression of major histocompatibility complex (MHC) molecules. As a result, CAR-expressing NK cells can eradicate heterogeneous malignancies that CAR T cells cannot, due to CAR T-cell dependence on MHC expression.8 Furthermore, NK cells are able to perform CD16-mediated anti- body-dependent cell-mediated cytotoxicity, giving them an added killing mechanism.8,9

CAR-NK cells also differ from CAR T cells by having a shorter lifespan in the blood-stream. Less potential for long-term off-tumor toxicities in CAR-NK cells is theorized as a result.9 Healthy cells express CD19 as well as malignant cells. While having CAR T cells remain in the body for longer periods may be associated with continued clinical benefit in maintaining remissions, when CAR T cells remain in the body for prolonged periods, this may also lead to B-cell aplasia and hypogammaglobulinemia, explained Riedell.

Additionally, preclinical and phase 1/2 trials have shown that allogeneic CAR-NK- cell infusions decrease the risk of GVHD.1,9,10 This allows the expansion of NK-cell production beyond autologous cells or only 1 cell line source. Persistence of allogeneic CAR NK cells has been observed in patients for at least 1 year despite HLA mismatching.11,12

Furthermore, NK cells can be administered without a requirement for full HLA matching.10 This allows for the use of allogeneic sources for CAR NK cells, including healthy donors, umbilical cord blood units, or induced pluripotent stem cells, Riedell noted. Importantly, manufacturing failures and out-of-specification products can also be avoided with off-the-shelf therapy.10

This allows for the use of allogeneic sources for CAR NK cells, including healthy donors, umbilical cord blood units, or induced pluripotent stem cells. Products are able to come off the shelf without the need to navigate collection of patients T cells and await their engineering and manufacture, which can take weeks, Riedell noted. Importantly, manufacturing failures and out-of-specification products can also be avoided with off-the-shelf therapy.10

CAR-NK cell therapy may be associated with a lower incidence and severity of CRS and neurologic toxicity, which is another reason this therapy is being explored, explained Riedell. These less severe adverse events may be due to the release of milder cytokines such as granulocyte-macrophage colony-stimulating factor and interferon-.9 CAR T cells induce the release of more cytotoxic cytokines, such as interleukin-1 (IL-1) and IL-6, that are associated with CRS.

Despite the safety and promising clinical efficacy of unmodified allogeneic NK cells, several challenges to using CAR-NK cells have emerged from clinical trials.

While CAR-NK cell therapy has been shown to be technically feasible, there is overall limited data in regard to the efficacy and safety of this treatment approach. Given that these cellular therapy products are allogeneic, there is a concern for emergence of graft-vs-host disease, Riedell said. There are many current clinical trials being conducted that evaluate CAR-NK cell therapy and we eagerly await the results of these trials to better understand the impact of this treatment approach, he added.

Furthermore, NK cells have a short lifespan of only 1 to 2 weeks, and without cytokine support, infused cells do not persist in the donor, which restricts efficacy.13

It is unknown if responses seen with this treatment may be durable and associated with continued remissions or if this therapy may be better utilized to induce responses and remissions in patients and then consolidate those remissions with an allogeneic stem cell transplant, explained Riedell.

Techniques to enhance the stability of CAR-NK cells include incorporation of transgenes encoding exogenous cytokines, such as IL-15.11 However, exogenous cytokines have undesirable adverse effects and can promote the activation of other immune sub- sets, such as regulatory T cells, which may suppress the effector functions of NK cells.14

Another challenge with CAR-NK cells is that NK cells are limited in number and often require ex vivo expansion and actiation. NK cells represent a minor fraction of peripheral blood leukocytes, and thus the generation of sufficient numbers of NK cells remains a major challenge for adoptive immunotherapy.

NK-92 is an established NK cell line that can be used as a source of cells for CAR- NK therapies, representing an alternative to patient- or donor-derived NK cells. An advantage of this process is easier manufacture of off-the-shelf CAR-NK products; however, a drawback is that NK-92 cells are from a tumor cell line and have a potential tumorigenicity risk.15

Lastly, CAR NK approaches are limited by approaches to gene transfer in NK cells. Gene transduction may lead to random intergration of DNA into the target cell genome, and can encourage off-target effects, including the silencing of essential genes or expression of tumor suppressor genes.9

Viral transduction results in low levels of transgene expression in NK cells and adversely impacts their survival. Nonviral vectors have been explored and are considered safe alternatives, but their relative overall benefits remain unclear.11

Several phase 1 and 2 trials for CAR-NK therapy are ongoing, with some published results.

In a phase 1/2 study (NCT03056339), patients with B-cell lymphoid malignancies were administered cord bloodderived, HLA-mismatched, anti-CD19 CAR-NK cells.12 The cells were transduced with a retroviral vector that expressed genes encoding anti- CD19 CAR, IL-15, and inducible caspase 9 (safety switch).

Of 11 heavily pretreated patients with CD19-positive lymphoma or chronic lymphocytic leukemia (CLL), 8 had an objective response (73%) and 7 had complete remission (64%) without major toxic effects. There were no recorded events of CRS, neurotoxicity, hemophagocytic lymphohistiocy- tosis, or GVHD.

Myelotoxicity was observed, which the investigators attributed to the lymphodeplet-ing chemotherapy prior to infusion. Many responses were seen within 30 days of infusion. Also, the CAR-NK cells expanded and persisted for at least 12 months.

A second study, a phase 1 trial (NCT04245722), evaluated the safety and efficacy of FT596, a multi-antigentargeted, pluripotent stem cellderived, off-the-shelf, anti-CD19 CAR-NK cell therapy. In the study, 20 heavily pretreated patients with relapsed/ refractory B-cell lymphoma or CLL were treated with FT596, either alone or in combination with rituximab (Rituxan).

Responses were seen in 8 of 11 efficacy-evaluable patients, 7 of which were complete respons- es. No GVHD or ICANS was observed in any of the 20 treated patients, and only 2 cases of CRS were reported.16

Several other clinical trials of interest are ongoing. A phase 1 study (NCT05247957) evaluating NKG2D, a cord bloodderived CAR-NK therapy, in patients with relapsed/refractory acute myeloid leukemia is expected to conclude at the end of 2022.

Another phase 1 study (NCT04887012) of HLA haploidentical anti-CD19 CAR-NK cells in relapsed/refractory B-cell non-Hodgkin lymphoma is ongoing. Finally, an early phase 1 study (NCT05215015) of CAR-NK cells targeting CD33 in patients with acute myeloid leukemia is ongoing.

CAR-NK cell therapy will likely become much more common and an area of increasing research focus should we be able to gain a better understanding that this treatment approach is safe and efficacious, Riedell noted. Additional studies are needed in order to understand optimal CAR-NK cell constructs, the best antigens to target, and strategies to bolster CAR-NK cell manufacturing, storage, and delivery, he added.

REFERENCES:

1. Basar R, Daher M, Rezvani K. Next-generation cell therapies: the emerging role of CAR-NK cells. Blood Adv. 2020;4(22):5868-5876. doi: 10.1182/bloodadvances.2020002547

2. FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. FDA. September 7, 2017. Accessed March 23, 2022. https://bit.ly/38mmisI

3. Maude SL, Laetsch TW, Buechner J, et al. Tisagenlecleucel in children and young adults with B-cell lymphoblastic leukemia. N Engl J Med. 2018;378(5):439-448. doi:10.1056/NEJMoa1709866

4. Sterner RC, Sterner RM. CAR-T cell therapy: current limitations and potential strategies. Blood Cancer J. 2021;11(4):69. doi:10.1038/s41408-021-00459-7

5. Wagner J, Wickman E, DeRenzo C, Gottschalk S. CAR T cell therapy for solid tumors: bright future or dark reality? Mol Ther. 2020;28(11):2320-2339. doi:10.1016/j.ymthe.2020.09.015

6. Morris EC, Neelapu SS, Giavridis T, Sadelain M. Cytokine release syndrome and associated neurotoxicity in cancer immunotherapy. Nat Rev Immunol. 2022;22(2):85-96. doi:10.1038/s41577-021-00547-6

7. Marofi F, Saleh MM, Rahman HS. CAR-engineered NK cells; a promising therapeutic option for treatment of hematological malignancies. Stem Cell Res Ther. 2021;12(1):374. doi:10.1186/s13287-021-02462-y

8. Farag SS, Caligiuri MA. Human natural killer cell development and biology. BloodRev. 2006;20(3):123-137.doi:10.1016/j.blre.2005.10.001

9. Xie G, Dong H, Liang Y, Ham JD, Rizwan R, Chen J. CAR-NK cells: A promising cellular immunotherapy for cancer. EBioMedicine. 2020;59:102975. doi:10.1016/j.ebiom.2020.102975

10. Lupo KB, MatosevicS. Natural killer cells as allogeneic effectors in adoptive cancer immunotherapy. Cancers. 2019;11(6):769.doi:10.3390/cancers11060769

11. Gong Y, Klein Wolterink RGJ, Wang J, Bos GMJ, GermeraadWTV. Chimeric antigen receptor natural killer (CAR-NK) cell design and engineering for cancer therapy. J Hematol Oncol. 2021;14(1):73. doi:10.1186/s13045-021-01083

12. Liu E, Marin D, Banerjee P. Use of CAR-transduced natural killer cells in CD19-positive lymphoid tumors. N Engl J Med. 2020;382(6):545-553. doi:10.1056/NEJMoa1910607

13. Malmberg KJ, Carlsten M, Bjrklund A, Sohlberg E, Bryceson YT, Ljunggren HG. Natural killer cell-mediated immunosurveillance of human cancer. Semin Immunol. 2017;31:20-29. doi:10.1016/j.smim.2017.08.002

14. Pedroza-Pacheco I, Madrigal A, Saudemont A,et al. Interaction between natural killer cells and regulatory T cells: perspectives for immunotherapy. Cell Mol Immunol. 2013;10(3):222-229.doi:10.1038/cmi.2013.2

15. Zhang C, Oberoi P, Oelsner S, et al. Chimeric antigen receptor-engineered NK-92 cells: an off-the-shelf cellular therapeutic for targeted elimination of cancer cells and induction of protective antitumor immunity. Front Immunol. 2017;8:533.doi:10.3389/fimmu.2017.00533

16. Bachanova V, Ghobadi A, Patel K, et al. Safety and efficacy of FT596, a first-in-class, multi-antigen targeted, off-the-shelf, iPSC-derived CD19 CAR NK cell therapy in relapsed/refractory b-cell lymphoma. Blood. 2021;138(suppl 1):823. doi:10.1182/blood-2021-151185

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CAR NK-Cell Therapy Is Quickly Growing in Immunotherapy - Targeted Oncology

Robert Vonderheide Appointed to Second Five-Year Term as Director of the Abramson Cancer Center

Robert H. Vonderheide has been appointed to a second five-year term as director of the Abramson Cancer Center (ACC) at the University of Pennsylvania, following a highly successful tenure that saw 17 FDA approvals in oncology for therapies based on studies led or co-led by ACC investigators, high-impact basic and translational research discoveries, expansion of radiation oncology services to new sites across the Philadelphia region, and development of new methods for live tumor imaging during surgeries. Under his leadership, the ACC has also launched new cancer home care and telemedicine programs, as well as initiatives that drove improvements in germline genetic testing, cancer screenings, and clinical trial participation by minority patients. Dr. Vonderheide will also continue in his roles as Vice President for Cancer Programs in the University of Pennsylvania Health System and Vice Dean for Cancer Programs in Penns Perelman School of Medicine.

In the next phase of his leadership, Dr. Vonderheide will build on the development of pathways to ensure that, amid the increasingly complex landscape of cancer care and research, patients across the entire health system are able to access leading-edge Penn Medicine care no matter where they live. Among key examples already underway: proton therapy at Lancaster General Health and Virtua Health in New Jersey, both set to open this year; sub-specialty surgery consultation at outpatient sites and Penn Medicines regional hospitals; and telemedical options for genetic counseling and CAR T cell therapy and bone marrow transplant evaluation and education.

Patients can expect an exceptional experience at every location across our health systema place they are cared for by the most committed staff, specialized nurses, and top physician experts, said University of Pennsylvania Health System CEO Kevin B. Mahoney. Now, we are harmonizing that patient experience to ensurethat every patient has the most seamless care and robust options across different sites of care, and the assistance to navigate easily between them. Under Dr. Vonderheides leadership, we are ensuring that every patient has every opportunity for the most personalized treatment and the very best chance at a cure through every door they enter across Penn Medicine.

Dr. Vonderheides renewal as ACC director includes a five-year, $130 million investment from the health system to provide resources and infrastructure to unify all missions of cancer care and research across Penn Medicine.

Growing access to cancer clinical trials is a key area of focus that will happen through the development of a cancer clinical trials network, including more opportunities for patients at Penn Medicines regional hospitals to participate in clinical trials being led at the ACCs main campus sites in Philadelphia, and the expansion of other trial sites closer to patients homes. Additional efforts will harness the power of Penns unified electronic health record, from new approaches to involve patients in the Penn Medicine BioBank to the expansion of programs providing patients with e-nudges to schedule mammograms and other tests and appointments through the MyPennMedicine portal.

This is a time of exciting, unprecedented momentum for cancer care and research, said J. Larry Jameson, dean of the Perelman School of Medicine and Executive Vice President of the University of Pennsylvania for the Health System. The cancer death rate has dropped faster in the past two years than ever before, due in part to the development of prevention strategies and of targeted and immunotherapies for an array of diseases. Dr. Vonderheide embodies that momentum as an exceptional collaborator who brings experts together across different disciplines to focus efforts on the most innovative ways to meet our shared goals of driving cancer discovery and improving patient care.

The ACC has continuously been designated as a Comprehensive Cancer Center by the National Cancer Institute (NCI) since 1974, one of 52 such centers in the United States. It is among the nations most highly ranked cancer centers, providing care to adults during more than 300,000 outpatient visits annually across the six-hospital Penn Medicine Cancer System, as well as delivering more than 190,000 outpatient infusion therapies, over 130,000 radiation treatments, and 330 stem cell transplants each year. The ACC was rated as exceptional during its competitive research funding review, the highest possible merit rating for an NCI Cancer Center.

Dr. Vonderheide is a leading authority in cancer immunology, leading a lab and clinical research focused on immunotherapies and vaccines for pancreatic, breast, and other cancers. He serves on the boards of directors of the American Association for Cancer Research, the Association of American Cancer Institutes, and the National Comprehensive Cancer Network. He is a member of the NCI Board of Scientific Advisors.

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This article was originally published here

ACS Pharmacol Transl Sci. 2022 Mar 30;5(4):193-206. doi: 10.1021/acsptsci.2c00019. eCollection 2022 Apr 8.

ABSTRACT

Prostate cancer (PCa) is one of the most frequently occurring cancers among men, and the current statistics show that it is the second leading cause of cancer-related deaths among men. Over the years, research in PCa treatment and therapies has made many advances. Despite these efforts, the standardized therapies such as radiation, chemotherapy, hormonal therapy and surgery are not considered completely effective in treating advanced and metastatic PCa. In most situations, fast-dividing tumor cells are targeted, leaving behind relatively slowly dividing, chemoresistant cells known as cancer stem cells. Therefore, following the seemingly successful treatments, the lingering quiescent cancer stem cells are able to renew themselves, undergo differentiation into mature tumor cells, and sufficiently reinitiate the disease, leading to cancer relapse. Thus, prostate cancer stem cells (PCSCs) have been reported to play a vital role in controlling the dynamics of tumorigenesis, progression, and resistance to therapies in PCa. However, the complete knowledge on the mechanisms regulating the stemness of PCSCs is still unclear. Thus, studying the stemness of PCSCs will allow for the development of more effective cancer therapies due to the durable response, resulting in a reduction in recurrences of cancer. In this Review, we will specifically describe the molecular mechanisms responsible for regulating the stemness of PCSCs. Furthermore, current developments in stem cell-specific therapeutic approaches along with future prospects will also be discussed.

PMID:35434534 | PMC:PMC9003388 | DOI:10.1021/acsptsci.2c00019

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Signaling Pathways and Targeted Therapies for Stem Cells in Prostate Cancer - DocWire News