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Verastem (VSTM) with star scientists in its advisory board and strong capital will be a good company to invest in. Among the scientific advisors is Robert Weinberg, discoverer of the first oncogene "ras", and is likely to contribute majorly to the company's aim of producing second generation chemotherapeutics that effectively kill cancer stem cells (CSCs). The current belief is that CSCs are involved in metastasis and recurrence of cancer and are not affected by current chemo regimens. Targeting these cells might abolish the ability of cancer to recur and metastasize far superiorly than current chemo regimens. They have strong preclinical data to support their development and these drugs are already in the clinical phase.

Here are some data figures to explain CSC theory/logic and its potential implications in cancer treatment. (All images taken from: Verastem R&D Day Presentation)

(click to enlarge)The current chemo regimens are reducing the tumor size but cannot kill CSCs efficiently which is resulting in tumor recurrence.

The current chemo regimens are reducing the tumor size but cannot kill CSCs efficiently which is resulting in tumor recurrence.

(click to enlarge)

The use of CSC drugs + current cancer treatments will result in tumor reduction and elimination of CSCs and so elimination of ability to recur.

The use of CSC drugs together with current cancer treatments will result in tumor reduction and elimination of CSCs and ability to cause recurrences.

There are three different pathways which maintain mammalian cells in CSC state: 1- Focal Adhesion Kinase (FAK) pathway, 2- PI3K-mTOR Pathway 3- Wnt Pathway. These pathways, activated in CSCs as well as in many of human cancer cell lines, are vital in keeping CSCs alive. VSTM focused on these pathways and their lead product, VS-6063, is an inhibitor of Focal Adhesion Kinase . It has been in clinical trials by Pfizer (PFE) where it was discovered and then was deprioritized due to portfolio review.

There are two possible reasons why Pfizer PFE has deprioritized its FAK program:

1. FAK inhibitors work efficiently only if cancer cells are negative for merlin (NF2) and merlin negative cancers are not very common. This limits the use of FAK inhibitors in many cancer patients who have a merlin-positive cancer.

Merlin hemizygosity (-/+) is a rare hereditary disease, also called neurofibromatosis type 2. The patients develop neuroectodermal tumors including ependimoma, schwannoma, meningioma which are known to commonly have merlin (-/-) mutation. These tumors can also arise sporadically in the population and again contain the merlin (-/-) mutation, but their incidence is really low. And again neurofibromatosis type 2 (merlin -/+) is a very rare disease.

Mesothelioma generally harbors merlin (-/-) mutations, with the mutation seen in half of mesothelioma tumor samples. But mesothelioma is another rare cancer type and its incidence has been decreasing steadily after strict regulations of absestosis use which is very significant cause of mesothelioma.

Let's take a look at common cancer types, like prostate cancer. Merlin expression was found to be low in LNCaP, PC3, 22RV1, and LAPC-4 prostate cancer cells. In DU145 cells, total and phosphorylated merlin were abundant, according to a study (PMID: 18361411).

In breast cancer, the merlin mutations have not been extensively studied but several studies that were carried out did not detect mutations in tumor tissues (PMID: 8069299 and 7493911). But there is one study which concluded loss of merlin in advanced breast cancer (PMID: 21965655)

We can infer that in breast and prostate cancer, there is no total absence of merlin in majority of patient tumor samples and cell lines but there is a decreased level of merlin found in these common cancers.

Here are two graphs showing you the effect of merlin expression on VS-4718 (FAK inhibitor) efficiency:

(click to enlarge)If there is no merlin, VS-4718 works well.

(click to enlarge)If there is no merlin, VS-4718 works well.

If there is no merlin, VS-4718 works well.

2. Serious side effects. This is less of an issue since cancer itself carries significant threats, any side effect that would require hospitalization (thrombocytopenia, etc.) can be tolerated. By comparison, many of the current chemo regimens have serious side effects resulting in hospitalization.

In mouse models, inactivation of focal adhesion kinase in cardiomyocytes promotes eccentric cardiac hypertrophy and fibrosis. A marked increase in tyrosine phosphorylation of FAK is also observed after treatment of cells with cholecystokinin, bombesin, vasopressin, and endothelin. So we can infer that FAK may mediate the effects of vasopression and endothelin and have a significant role in cardiomyocytes. We cannot predict human response but like I mentioned, even if a side effect occurs resulting in hospitalization, it is not likely that this will affect the progression of the drug as long as it works efficiently. In a phase I study of VS-6063 (conducted by Pfizer) there were no significant side effects other than unconjugated hyperbilirubinemia. The graph below shows you the common side effects of VS-6063:

(click to enlarge)There is no significant side effect other than unconjugated hyperbilirubinemia.

The company is now running a Phase I trial with its FAK inhibitor VS-6063 on ovarian cancer (NCT01778803). There is no study yet investigating merlin (-/-) mutation frequency in ovarian cancer but loss of heterozygosity of 22q (where merlin is located) is very common (71%) in ovarian cancers, which can cause decreased levels of merlin which, in turn, can increase the efficiency of FAK inhibitors. Loss of 22q is present in %11-38 of breast cancers, %21-50 of colon cancers, %33 of liver cancers.

We do not know the percentage of merlin (-/-) cancers exactly, but negative effect of merlin on FAK inhibitors will definitely decrease the usage of FAK inhibitors and may prevent FAK inhibitors to become a blockbuster cancer drug. This can explain why Pfizer PFE has deprioritezed its FAK program. But a curative cancer drug can easily become a blockbuster if it does its job very well, like imatinib.

VSTM's compounds in clinical trials are limited to FAK inhibitors for now; we will see how their Wnt and PI3K-mTOR inhibitors progress in clinical phases. 2013-2015 will be challenging years for VSTM because clinical data of their FAK inhibitors will be obtained after a round of trials in 2013-2015. We have yet to see whether or not this model efficiently working on CSCs works just as well within the human body.

Source: Verastem's Focal Adhesion Kinase Inhibitors And Their Great Potential