Will Mesothelioma Finally Meet Its Match?
Malignant pleural mesothelioma, which affects the tissue surrounding the lungs, is a highly aggressive, asbestos-related cancer with limited treatment options. Buta new clinical trial hopes to prove that researchers have found the key to halting progression and recurrence of this relatively rare cancer.
Currently, treatment of malignant pleural mesothelioma, the most common type of mesothelioma, includes surgery, chemotherapy and radiation – often a combination of the three therapies. Even with treatment, recurrence of mesothelioma is likely.
Resilient Stem Cells Appear to Promote Cancer Recurrence
While tumors are made up of many types of cells, research has shown that the presence of mesothelioma stem cells are a major factor in tumor resistance to chemotherapy, recurrence and disease progression.So, although the tumor may shrink with a “first line” treatment such as chemotherapy, stem cells appear to be resistant to the treatment and remain in the body prompting the tumor to regrow. No standard second line treatment targeting reoccurrence exists today.
A new clinical trial called COMMANDis testing what Professor Dean Fennell, Chair of Thoracic Medical Oncology at University of Leicester calls a novel “two-hit strategy.”The study will be evaluatingdefactinib (VS-6063), an oral therapy designed to target production of cancer stem cells. Following chemotherapy treatment, patients will be given defactinib, which is designed to target the remaining stem cells.
Targeted Therapies are the Present & Future for Many Types of Cancer
Defactinibis an example of a biological “targeted therapy.” Targeted therapies are a focal point ofcurrent cancer treatment and drug development. Targeted therapies focus on a cancer’s specific molecular profile to help the body fight the disease. For example, some targeted therapies inhibit the activity of certain enzymes, proteins or other molecules involved in the development and spread of cancer cells.
Many types of cancers including lymphoma, melanoma, leukemia and others are being treated with FDA approved targeted therapies. Additional therapies are under investigation to treat other types of cancer. Although some drugs effectively treat more than one type of cancer, most targeted drugs are developed to treat a specific type.
Targeted therapies can work in different ways, but the idea behind them is that they attack the cancer cells more effectively and with less damage to healthy cellsas compared to traditional treatment methods. Unlike chemotherapy, which indiscriminately kills both cancer cellsand healthy cells, targeted therapies are designed to utilize the body’s own immune system to stop cancer cells from multiplying or kill cancer cells only (not healthy cells). Hence, the idea that they act on specific targets associated with the cancer.
Defactinib, the oral therapy being studied in the Phase II COMMAND clinical trial,targets cancer stem cells by inhibiting the process of focal adhesion kinase (FAK). FAK is critical for cancer stem cell survival. For a tumor to start growing, stem cells go through a process that is mediated by FAK.
Presently, there are no targeted therapies being used to treat malignant pleural mesothelioma, though many are being studied. Two other companies are in active clinical trials that focus on FAK:Boehringer Ingelheim (Phase I) and GlaxoSmithKline (Phase 1b).
What Can Merlin Teach Us About Cancer Tumor Development?
Targeting specific biological processes to kill cancer cells may sound relatively straightforward, but there are so many different interactionsoccurring inside the body at a molecular level that it makes it extremely difficult to isolate specific causes and effects.
To figure out what to target, researchers mustidentify and understand the interactions between specific cancer genes and proteins and the tissue environment that is promoting the cancer cell growth and survival.
In the case of malignant pleural mesothelioma, research has identified mutations in particular genes that help regulate the normal cycle of cell growth and cell death. The mutations prevent those genes from doing their job of suppressing tumors. As a result, the normal cell cycle is interrupted and cancer cells are free to grow.
Inactivation of one of the suppressor genes mentioned above called NF2 has been linked to low merlin levels. Merlin is a protein that serves as a tumor suppressor. Recent research published in Cancer Research (February 15, 2014) and Science Translational Medicine (May 21, 2014) has found that low merlin levels paired with the inactivation of the tumor suppressor genes cause tumors to grow more aggressively. Approximately half of mesothelioma tumors have been found to have low merlin levels.
So, the bull’s-eye for a targeted mesothelioma therapy appears to be the signaling pathway (FAK). That is precisely what defactinib has been developed to target and what the COMMAND trial is designed to test.The study also seeks to understand the role that merlin plays in tumor regrowth. Trial patients will be subdivided into low and high merlin groups then randomized to receive the drug or placebo in order to learn more about the role of merlin loss in tumor development.
COMMAND Study Enrolling Malignant Pleural Mesothelioma Patients
The COMMAND study is a Phase II clinical trial seeking to enroll approximately 400 patients with malignant pleural mesothelioma at 32 clinical sites in 12 countries including the US, UK, Japan, Australia, Canada, South Africa, New Zealand and Europe.Verastem expects the study to be fully enrolled by the second half of 2015.
Eligible patients, previously treated with chemotherapy, will be categorized by high or low merlin levels and randomized to receive either placebo or defactinib.
Defactinib is a stem cell inhibitor currently being studied in other clinical trials for the treatment of ovarian and small cell lung cancerwith promising outcomes to date. The drug was designed to stop signals that give certain cancer cells the go-ahead to divide and grow. This is the first time that a drug will be tested to inhibit a particular protein in the mesothelioma cancer stem cells.The goals of the study (“primary endpoints”)are to halt progression of the cancer and increase patients’ lifespans and quality of life.
Mesothelioma Patients Must Meet Criteria to Participate in Clinical Trial
To be eligible for the study, patients must meet certain criteria including but not limited to:
- Histologically confirmed (microscopic examination of tissue) malignant pleural mesothelioma that is not metastatic or unresectable.
- Eligible to undergo excisional surgery.
- Localized disease confined to one affected hemithorax.
- Normal pulmonary, cardiac function, renal, hepatic hematologic and performance functions.
- Male or non-pregnant female
- Eighteen years of age or older
In addition to these inclusion criteria, there are also a number of exclusion criteria, which are detailed on the study website.
COMMAND is sponsored by Verastem, Inc. of Cambridge, MA. Verastem is a biopharmaceutical company that develops drugs that target and kill cancer stem cells.
Raphael Bueno, M.D. Chief of Thoracic Surgery at Brigham and Women’s Hospital in Massachusetts is the Principal Investigator. Dr. Bueno’s clinical and research interests include finding new ways to diagnose and treat all forms of thoracic (heart, lungs, esophagus, and other organs in the chest) cancers including mesothelioma.