Researchers and physicians at the Herbert Irving Comprehensive Cancer Center are exploring the use of a new targeted therapy for a rare type of cancer.
Soft tissue sarcomas are a rare cancer with approximately 14,000 new diagnoses in the United States each year. Sarcoma is a heterogeneous cancer type that includes over 50 different subtypes, each with a unique biology that requires researchers and clinicians to develop a specific understanding of how it works. Because of this rarity and heterogeneity, sarcoma is a particularly difficult disease to diagnose and treat. Advances in treatments for sarcoma have lagged, in part due to the difficulty in enrolling enough patients in clinical trials to find new effective therapies.
Dr. Matthew Ingham, Assistant Professor of Medicine at Columbia University Vagelos College of Physicians and Surgeons, is working to change this by leading a new clinical trial that explores a novel combination of a targeted therapy plus chemotherapy for patients with uterine leiomyosarcoma (LMS). This innovative clinical trial, sponsored and supported by the National Cancer Institute’s Cancer Therapy Evaluation Program (NCI CTEP), will mark the first-time PARP inhibitors —which have proven effective in certain forms of ovarian and breast cancer – are tested in a specific subtype of sarcoma.
Recent research suggests that uterine LMS exhibits characteristics of “BRCAness,” a certain form of deficiency in the ability to repair damaged DNA which makes these cancer cells especially sensitive to a class of drug called PARP inhibitors. Until this new clinical trial, the challenge has been identifying the specific sarcoma subtype and combination therapy with a PARP inhibitor that would be the most effective for sarcoma patients.
Q: Why could PARP inhibitors, which have proven successful as breast cancer and ovarian cancer therapies, be successful in sarcoma patients?
PARP inhibitors are targeted drugs that induce certain forms of DNA damage in cancer cells. Specifically, PARP inhibitors can lead to double-stranded breaks in DNA, particularly when given with certain types of chemotherapy. Double-stranded DNA breaks are very toxic to cells if not repaired quickly. Some cancer cells have intrinsic defects in their ability to repair double-stranded DNA breaks. Cells with a mutation in the BRCA gene were first identified to have such a vulnerability. But scientists now realize that other genes are involved in addition to BRCA, and cancers with this vulnerability are said to have “BRCAness”. Recent research from many independent groups suggests that uterine LMS has features of BRCAness, just like ovarian and breast cancers, where PARP inhibitors are now approved in certain settings. These findings led to the excitement to test PARP inhibitors in uterine LMS.
Q: How did research at Columbia further explore the use of PARP inhibitors for sarcoma?
Research from the lab of Dr. Gary Schwartz, deputy director of the Herbert Irving Comprehensive Cancer Center, demonstrated that while most uterine LMS models are not very sensitive to PARP inhibitors when given alone, the combination of low-dose DNA-damaging chemotherapy in combination with a PARP inhibitor is dramatically effective at suppressing uterine LMS cancer growth. Additional research from Dr. Schwartz’s lab showed that temozolomide is the best chemotherapy partner for olaparib and also elucidated how the drug combination may work. Specifically, the combination likely works by inducing the form of DNA damage that uterine LMS cancer cells are intrinsically unable to repair, and when exposed to this treatment, the cancer cells die.
Q: Why is it difficult to find new treatments for sarcomas?
There are many unique challenges for developing effective new treatments for sarcoma. Sarcoma is a rare disease, which makes it difficult to enroll enough patients onto clinical trials. That is why collaboration across academic medical centers is essential. To make things even more complicated, the different subtypes of sarcoma are biologically distinct – in other words, a new therapy may work in one subtype, but not in another. Because of this heterogeneity, it’s important to understand each subtype and test new treatments specifically for that subtype to achieve the best results for patients. Unfortunately, because of these challenges, there is often limited interest in sarcoma from pharmaceutical companies, which provide a major part of the support needed to conduct clinical trials, as compared more common types of cancer.
Q: How will this trial be coordinated across multiple institutions?
This clinical trial is sponsored by the National Cancer Institute’s Cancer Therapy Evaluation Program (NCI CTEP). The trial will be run through a network of collaborating institutions formed by the NCI, the Experimental Therapeutics Clinical Trials Network (ETCTN), which aims to efficiently evaluate novel early phase cancer treatment approaches. The selection of a trial by CTEP is a competitive process - less than a third of proposals are accepted - and is based on the quality of the preclinical research and the design of the clinical trial. There is an emphasis on clinical trials based on translational research using tissue biopsies and blood obtained during the trial that will build on our understanding of the cancer, how the treatment works, and for which patients it may be most effective. Running the trial through the ETCTN will allow this new combination therapy to be available at many sarcoma referral centers in the United States and expand its reach to as many patients as possible.
More information about this clinical trial, including how to enroll, can be found here.
Dr. Matthew Ingham was recently awarded a Career Development Award from the Sarcoma Foundation of America through the Conquer Cancer Foundation, a philanthropic arm of the American Society of Clinical Oncology (ASCO). Funding for this clinical trial is partially supported from this award.
--Kristina F. Mesoznik