CAMBRIDGE, Mass.--(BUSINESS WIRE)--

Verastem, Inc., (VSTM) a clinical-stage biopharmaceutical company focused on discovering and developing drugs to treat cancer by the targeted killing of cancer stem cells, announced that Robert Weinberg, Ph.D., Verastem scientific cofounder and chair of the Scientific Advisory Board, and Christoph Westphal, M.D., Ph.D., Verastem cofounder, Chairman and CEO, will present at the MIT Technology Breakfast on February 28, 2013, at 8am ET.

The Technology Breakfast series features breakthrough discoveries from research at MIT and brings together the researchers and entrepreneurs who accelerate and commercialize the technology. Drs. Weinberg and Westphal will speak on how they are changing the landscape of the current treatment paradigm in cancer.

Verastem was founded on work in the laboratories of Dr. Weinberg and Dr. Eric Lander, of the Broad Institute of MIT and Harvard, that describes the underlying mechanisms of cancer stem cell development and methods to identify drugs that preferentially target them. Cancer stem cells have been implicated as a cause of tumor resistance to chemotherapy and driver of disease progression.

Verastem has advanced the discoveries made by Drs. Weinberg and Lander into clinical development and is currently testing lead compound, VS-6063, in a Phase 1/2 clinical trial for ovarian cancer in combination with the standard chemotherapy, paclitaxel. VS-6063 is an orally available, small molecule inhibitor of focal adhesion kinase (FAK).

Verastem is planning a potentially pivotal trial of VS-6063 in mesothelioma midyear 2013. In addition to VS-6063, the Company has multiple drugs targeting cancer stem cells in development. Verastem plans to initiate clinical trials of FAK inhibitor VS-4718 and PI3K/mTOR inhibitor VS-5584 during 2013 in patients with advanced cancers.

Dr. Robert Weinberg is a founding member of the Whitehead Institute for Biomedical Research and the Daniel K. Ludwig Professor for Cancer Research in the Department of Biology at MIT. Dr. Weinberg is an internationally recognized authority on the genetic basis of human cancer development and is the author or editor of five books and more than 350 articles. The Weinberg lab is known for its discovery of the first human oncogene -- the ras oncogene that causes normal cells to form tumors -- and the isolation of the first known tumor suppressor gene -- the Rb gene. He earned his S.B. and Ph.D. in biology/life science from MIT. Dr. Weinberg is a member of the National Academy of Sciences, the Institute of Medicine and a Fellow of the American Academy of Arts and Sciences.

Dr. Christoph Westphal cofounded Verastem and is the Chairman and Chief Executive Officer of the Company. Dr. Westphal is a partner of Longwood Fund, which founds and invests in medical companies. He was founder and chief executive officer of Sirtris Pharmaceuticals, which he took public and led as chief executive officer until 2010. Christoph cofounded Alnara Pharmaceuticals (acquired by Eli Lilly in 2010) and was cofounder and chief executive officer of Alnylam Pharmaceuticals and Momenta Pharmaceuticals. Currently, Dr. Westphal serves on the board of directors of Ovascience (which he cofounded), on the Board of Fellows of Harvard Medical School and on the Board of Overseers of the Boston Symphony Orchestra. He earned an M.D. from Harvard Medical School, Ph.D. in genetics from Harvard University and BA, summa cum laude and Phi Beta Kappa, from Columbia University.

About Verastem, Inc.

Verastem, Inc. (VSTM) is a clinical-stage biopharmaceutical company focused on discovering and developing drugs to treat cancer by the targeted killing of cancer stem cells. Cancer stem cells are an underlying cause of tumor recurrence and metastasis. Verastem is developing small molecule inhibitors of signaling pathways that are critical to cancer stem cell survival and proliferation: FAK, PI3K/mTOR and Wnt. For more information, please visit http://www.verastem.com.

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Verastem Cofounders to Present at MIT Technology Breakfast on Breakthrough Discoveries in Cancer Stem Cells

The expression of Ski-related oncogene N (SNON) prior to (left) and after (right) the onset of differentiation. Credit: 2012 Cold Spring Harbor Laboratory Press

Researchers at the A*STAR Institute of Medical Biology (IMB) have discovered a critical checkpoint protein that controls when human embryonic stem cells (hESCs) begin to differentiate.

The Nodal/Activin signaling pathway is an important regulator of hESC fate. Signaling molecules in this pathway trigger the downstream proteins SMAD2 and SMAD3 to activate a transcription factor known as NANOG, as well as other core pluripotency proteins. These regulatory factors, in turn, ensure that the self-renewing hESCs remain capable of forming all cell types in the embryo and avoid differentiation. When differentiation is triggered, however, the role of this signaling axis changes, and the very same pathway begins to drive the formation of primitive cell types, namely the mesoderm and endoderm.

To explain these contrasting effects of Nodal/Activin signaling, a team led by the IMB's Ray Dunn explored the role of repressor proteins in the pathway. "We reasoned that one explanation for why hESCs do not differentiate in the presence of Nodal/Activin is the existence of repressor proteins that decorate the regulatory elements of differentiation genes and turn them off," Dunn explains. "In my lab, we identified one such repressor that fits this bill, [it is] called SNON."

SNON, an abbreviation of Ski-related oncogene N, is a potent repressor of SMAD2 and SMAD3 and, as Dunn's team showed, is abundant in undifferentiated hESCs, but only at the promoters of differentiation genes. At the onset of differentiation, SNON is destroyed by the proteasome, the cell's clean-up machinery for unwanted proteins. SNON levels then drop precipitously (see image), which allows SMAD2 and SMAD3 to cooperate with other transcription factors involved in the determination of cell fate, including FoxA2. This leads to the formation of early mesoderm and endoderm, two of the three primitive germ layers.

"Our research shows that when hESCs begin to differentiate, SNON is targeted for degradation," says Dunn. This finding is consistent with many studies of cancer cell lines, which, like hESCs, retain the ability for continuous proliferation and also have elevated levels of SNON.

One outstanding question, according to Dunn, remains the identity of the molecules that target SNON for degradation. A protein called ARKADIA is one suspect. ARKADIA is known to regulate SNON stability in a cell type-dependent fashion, but its role in embryonic stem cells remains unclear. "Follow up experiments in our lab aim to determine whether ARKADIA acts alone or collaborates to degrade SNON in hESCs," says Dunn.

More information: Tsuneyoshi, N., et al. The SMAD2/3 corepressor SNON maintains pluripotency through selective repression of mesendodermal genes in human ES cells. Genes & Development 26, 24712476 (2012). genesdev.cshlp.org/content/26/22/2471.abstract

Journal reference: Genes & Development

Provided by Agency for Science, Technology and Research (A*STAR), Singapore

Continued here:
Stem cells: Keeping differentiation in check

Induced pluripotent stem cells could soon be used in human trials in Japan.

Kathrin Plath lab, Univ. Calif. Los Angeles/CIRM

In the seven years since their discovery, induced pluripotent stem (iPS) cells have transformed basic research and won a Nobel prize. Now, a Japanese study is about to test the medical potential of these cells for the first time. Made by reprogramming adult cells into an embryo-like state that can form any cell type in the body, the cells will be transplanted into patients who have a debilitating eye disease.

Masayo Takahashi, an ophthalmologist at the RIKEN Center for Developmental Biology in Kobe, Japan, plans to submit her application for the study to the Japanese health ministry next month, and could be recruiting patients as early as September. Stem-cell researchers around the world hope that if the trial goes forward, it will allay some of the safety concerns over medical use of the cells. And the Japanese government hopes that its efforts to speed iPS cells to the clinic by generously funding such work will be vindicated (see Nature 493, 465; 2013).

The entire field is very dependent on this group and the Japanese regulatory agencies to ensure that preclinical evidence for safety and efficacy is very strong, says Martin Pera, a stem-cell expert at the University of Melbourne in Australia.

Takahashi, who has been studying the potential of iPS cells to rebuild diseased tissue for more than a decade, hopes to treat around six people who have severe age-related macular degeneration, a common cause of blindness that affects at least 1% of people aged over50. The form of the disease that Takahashi will treat occurs when blood vessels invade the retina, destroying the retinal pigment epithelium that supports the light-sensitive photoreceptors. This form can be treated with drugs that block the growth of new blood vessels, but these often have to be injected repeatedly into the eye.

Takahashi will take a peppercorn-size skin sample from the upper arm and add proteins that reprogram the cells into iPS cells. Other factors will transform the iPS cells into retinal cells. Then a small sheet of cells will be placed under the damaged area of the retina, where, if things go well, the cells will grow and repair the pigment epithelium.

The researchers hope to see the transplants slow or halt the disease, but their main goal is to show that the cells are safe. One concern is that the reprogrammed cells will trigger an immune reaction as has been seen in mice (T.Zhao etal. Nature 474, 212215; 2011). But that concern has faded after a recent study suggested that iPS cells did not provoke an immune reaction after all (see R. Araki et al. Nature 494, 100104; 2013 and Nature 493,145; 2013). Immune compatibility seems to be as expected, so I am not so concerned about that issue, says stem-cell expert George Daley of Harvard Medical School in Boston, Massachusetts.

A bigger worry is that the reprogrammed cells might multiply uncontrollably and form tumours instead of healthy tissue. But Pera and Daley are reassured by the pre-clinical data that Takahashi has presented at conferences. Takahashi says that these results, submitted for publication, show that her iPS cells do not form tumours in mice and are safe in non-human primates.

Pera adds that the procedure to treat macular degeneration requires just a few stem cells, reducing the chances that a tumour will form. Also, any tumours would be relatively easy to remove because the eye is more accessible than some organs.

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Stem cells cruise to clinic