Drug Combo to Combat Mesothelioma

Cancer stem cells help your mesothelioma resist chemotherapy and grow back after surgery, but a drug combination now in Phase 1 clinical trials seeks to prove those stem cells can be thwarted.

The drug combination brings together the compounds VS-5584 and VS-6063, both discovered and developed by the biotech firm Verastem, Inc. VS-5584 is a dual mTORC1/2 and PI3K inhibitor. Defactinib — VS-6063 — is an inhibitor of focal adhesion kinase, abbreviated FAK.

The clinical trial of the drug combination began dosing the first of an expected 56 U.S. and British patients in January.

Enrollments are still being accepted. To qualify, you must of course have mesothelioma, but also mesothelioma that recurred following surgery or chemotherapy.

Because this is just a Phase 1 trial, the company is conducting it with the aim of assessing the drug combination’s safety, pharmacokinetics and pharmacodynamics.

Assessing the drug combination’s clinical activity will also be part of the trial, but it won’t be front and center. Clinical activity becomes the focus in the next study, Phase 2.

Promising Treatments Against Mesothelioma

Earlier, Verastem reported promising results from the tests they conducted with VS-5584 and VS-6063. The tests examined the drugs apart and in combination using lab-based preclinical models.

Although VS-6063 comes after VS-5584 in numerical label order, VS-6063 is actually farther along in its development than is VS-5584. In fact, the clinical trial amounts to the third big mesothelioma-specific test of VS-6063, according to the company.

Verastem officials indicate that VS-6063 is designed as a switch maintenance therapy for use on the heels of frontline chemotherapy.

They say they have been encouraged by its biomarker responsiveness. In particular, they credit VS-6063 with having caused a significant amount of mesothelioma tumor shrinkage less than two weeks after administration.

Taken orally, VS-6063 targets cancer stem cells. When it finds them, VS-6063 disrupts the activity of those cancer stem cells by inhibiting FAK — focal adhesion kinase.

The company says that cancer stem cells flourish when they are able to draw upon adequate FAK activity.

Like VS-6063, VS-5584 is taken orally. Its function is to reduce the percentage of cancer stem cells and induce tumor regression by selectively inhibiting class 1 PI3K enzymes.

VS-5584 also selectively inhibits the proteins known as mechanistic target of rapamycin complex 1 and complex 2 — mTORC1 and mTORC2, respectively.

VS-5584 is currently in a Phase 1 clinical trial of its own. Verastem reports that the first patients enrolled have by this point been taking VS-5584 for more than six months.

The company indicates that the patients are by and large tolerating VS-5584 well. None has yet been given the maximum tolerable dose, but already there are signs of it working.

Another indication of the promise of VS-5584 came earlier in January when the European Commission awarded the compound orphan medicinal-product designation as a mesothelioma therapeutic.

Verastem explains that the orphan designation is given to drugs that “may provide significant benefit to patients suffering from rare diseases.”

The designation allows the European Medicines Agency to step in and help an orphan drug’s maker put together clinical trials. The agency also offers regulatory and monetary assistance in getting the drug formally and fully approved.

Mesothelioma Drugs’ Synergistic Effect

In the clinical trial combining VS-6063 and VS-5584, the company says it hopes to create a synergy between the two compounds.

According to Verastem, VS‐6063 and VS‐5584 — when tested individually in vivo for reduction of mesothelioma tumor growth — gave indications that they might work even better if paired.

The Verastem company discovers and develops drugs to treat cancer by the targeted killing of cancer stem cells. Its biggest products are small-molecule inhibitors of signaling pathways that are critical to cancer stem cell survival and proliferation.