Killing Cancer Stem Cells: The Final Battle?

| About: Verastem (VSTM)

Cambridge, MA based Verastem (NASDAQ:VSTM) is a pioneer in the battle against cancer stem cells.

Cancer drugs in use today are successful in killing the bulk of tumor cells, but most of the time fail to result in a durable clinical solution because the cancer returns. A reason for this failure may be the presence of a small minority of cells in the tumors called CSCs (cancer stem cells), which are resistant to existing therapies.

Cancer stem cells may be few in numbers in the tumor but are able to travel anywhere in the body and metastasize; that is, initiate new tumors. Metastatic tumor sites are the cause of death in more than 90 percent of cancer patients. Cancer stems cells have been found in many types of tumors, including leukemia, myeloma, breast, prostate, colon, brain, lung and others.

The existence of CSCs is a fairly recent discovery (in the past 5 years) and the fight against them is led by a few pioneering companies, among them Verastem.

Cancer stem cells

Robert Weinberg, Ph.D., a professor at MIT and scientific co-founder of Verastem, explains in a videotaped lecture that killing cancer stem cells requires a totally different set of drugs than killing non-stem cells, and both sets of drugs are important and necessary.

Dr Weinberg said:

"I would say that, for many kinds of solid tumors, truly durable clinical responses will have to come from eliminating both the cancer stem cells in the tumor and the non-stem cells. Eliminating only one or the other will not suffice because the dynamics of cancer regrowth will ensure that sooner or later one will have a clinical relapse."

A major factor preventing the discovery of drugs against cancer stem cells in the early days was that these cells are few in numbers, difficult to isolate and when isolated, are unstable in culture. All that made it difficult to screen drugs against them.

Verastem's scientific co-founders, Robert Weinberg, Eric Lander, and Piyush Gupta, have discovered EMT (epithelial-to-mesenchymal transition). EMT is the process by which ordinary cancer cells are transformed into active and aggressive cancer stem cells and can be multiplied.

Using that process, a large number of stable cancer stem cells can be generated and screened by high-throughput drug discovery systems to find drugs that work against them. At MIT 16,000 different chemical compounds were screened and found that only a small number of those compounds, including salinomycin and etoposide, are effective in targeting and killing cancer stem cells.

Salinomycin happens to be a widely used antibacterial agent added to chickenfeed by farmers.

Piyush Gupta and colleagues have shown that salinomycin can kill breast cancer stem cells in mice 100 times more effectively than the standard of care chemotherapy drug paclitaxel.

Treatment of mice with salinomycin inhibited mammary tumor growth and showed potent antiproliferative activity against the drug-resistant cancer cell lines.

Using salinomycin as a cancer drug has a number of skeptics in the scientific community, as it is a decades-old drug, which is toxic when used in larger volume and may have patent problems.


To speed up corporate progress, in 2012 Verastem acquired the compound defactinib from Pfizer (NYSE:PFE) after a Phase 1 trial with 36 patients was successfully concluded.

Verastem has paid Pfizer for the drug $1.5 million upfront along with 192,012 shares of Verastem's shares and a further pledge of up to $125 million in milestone payments and royalties.

Defactinib (( VS-6063)) is Verastem's lead compound. It is currently tested in several trials: a Phase 2 trial called COMMAND, in mesothelioma, a Phase 1/1b study in ovarian cancer, a Phase 1 study in Japan and a Phase 2 trial in KRAS-mutated NSCLC (Non-Small Cell Lung cancer).

The COMMAND trial is a randomized, double-blind, placebo-controlled, multicenter study in patients with MPM (malignant pleural mesothelioma) who have not progressed following 4 cycles of treatment with chemos Alimta/cisplatin or Alimta/carboplatin.

200 mg defactinib tablets are given to these patients twice a day, or matched placebo.

The patients will continue to receive treatment until disease progression or other discontinuation criteria are met. All participants will be followed for overall survival by telephone contact every 2 months until end of life or the close of the study.

The COMMAND trial will be conducted at clinical sites in 11 countries enrolling about 350-400 patients. Defactinib inhibits FAK (focal adhesion kinase) pathway, which is critical for the growth and survival of cancer stem cells. The drug disrupts communication between cells in order to prevent mesothelioma cells from migrating to new locations in the body and metastasize.

A study published in The Journal of Cell Biology showed a reduction in metastasis in breast cancer patients when FAK was removed. The hope is that it will do the same for the metastasis of mesothelioma cells.

Throughout the years lung cancer has proven to be a most difficult target.

The first-line treatments, chemotherapies cisplatin and Alimta (made by Eli Lilly (NYSE:LLY), are not effective enough to improve survival times for patients. That is, reducing the primary tumor does not go far enough to prevent the spread of the cancerous cells.

The incidences of pleural mesothelioma have been steadily increasing worldwide. Pleural mesothelioma is often diagnosed in people who have been exposed to high levels of asbestos. The disease affects the pleura, a thin membrane of lubricating cells that lines the lungs and chest wall. It sometimes takes 10 years or more for symptoms to appear.

If defactinib can significantly increase progression-free and overall survival among patients, this will be the first effective mesothelioma drug ever to be used for maintenance therapy. This means the prospect of more cases of mesothelioma going into remission, and the potential to develop personalized treatment.

In July the FDA has granted defactinib an Orphan Drug Designation for use in the treatment of mesothelioma. Verastem owns patents covering the composition of matter for defactinib through 2029.


There are other companies working to develop therapies targeting cancer stem cells. There are at least eight CSC-focused competitors, including divisions of large pharmaceutical companies like Astellas Pharma Inc. (OTCPK:ALPMF), Sanofi (NYSE:SNY), GlaxoSmithKline (NYSE:GSK), Boehringer Ingelheim, Pfizer and others.

There are also smaller biotechnology companies that are developing therapies against CSCs, including OncoMed Pharmaceuticals (NASDAQ:OMED), Boston Biomedical Inc. and Stemline Therapeutics (NASDAQ:STML). Some of these competitors already have clinical data in hand.

Investors' summary

As of June 30, Verastem had cash and cash equivalents of $78.0 million compared to $84.4 million at the end of March and $91.5 million at the end of December 2012.

From an equity offering in July Verastem received $59.8 million in net proceeds, so in total the company has $137.8 million to fund operations.

Net loss for the second quarter was $10.3 million, or $0.49 per share, as compared to net loss of $6.8 million, or $0.34 per share, for the same period in 2012. Net loss includes stock-based compensation expense of $2.7 million for the second quarter.

The number of outstanding shares as of July 31, was 25,593,992. The 52 weeks range of the stock price was $6.25 to $18.82, and market cap is $272.58 million.

Confidence in the company by its management was shown by the fact that in June four top executives purchased nearly a half million worth of Verastem stock.

Last year Verastem raised $55 million during its initial public offering despite having no drugs in clinical trials at that time.

Its chairman and CEO Christoph H. Westphal M.D., is considered a maverick in the biotech business. Earlier in his career he launched the company Sirtris and sold it to GlaxoSmithKline for an amazing $720 million, and GSK has stood by the company even as researchers have raised questions over the science involved. After that he had a brief stint as the head of SR One, GSK's investment arm. Later he founded Longwood Founders Fund, a venture capital firm, which had a 15.4 percent stake in Verastem.

Verastem has a revolutionary idea, top cancer scientists are its co-founders and a maverick is its business leader. But it will need all the muscles it can muster in a major fight against what may turn out to be cancer's last stand.

Disclosure: I have no positions in any stocks mentioned, and no plans to initiate any positions within the next 72 hours. I wrote this article myself, and it expresses my own opinions. I am not receiving compensation for it (other than from Seeking Alpha). I have no business relationship with any company whose stock is mentioned in this article.