NFCR Basic Research in Action: Precision Medicine

Although cancer research is ultimately about finding a cure for cancer, it also encompasses efforts to make cancer a more manageable disease with less toxic side effects.

Decades of research led us to a new era in the treatment of cancer known as precision medicine or precision oncology. Gone are the days of the “one-size fits all” approach to cancer treatment. Instead, doctors are beginning to administer treatments based on the needs of each individual person, their genetic information, health history and specific conditions. The goal of precision medicine is to target the right treatments to the right patients at the right time.

Dr. Daniel A. Haber’s laboratory focuses on understanding the genetic abnormalities of cancer and the research aims to guide targeted drug therapies. His lab is responsible for identifying a specific mutation in the epidermal growth factor receptor (EGFR) in a subset of NSCLC. By linking EGFR mutations to lung cancer, Dr. Haber made it possible to identify patients who will respond well to certain cancer-fighting drugs that block EGFR mutations. In July 2016, the FDA approved the drug Iressa® as a front-line treatment for patients with these specific tumor mutations that Dr. Haber identified. Currently, his lab is defining the genes and proteins that contribute to the dormancy (resting state) of breast cancer cells and the awakening of the cells decades later after the cancer was removed. Ultimately, therapeutic strategies will be developed to target these key genes and proteins with the aim to prevent the distant metastatic recurrence of cancer after surgery.

Dr. Wei Zhang has devoted his entire career to the pursuit of precision oncology – specifically to the key molecular and genomic events that drive the development and progression of cancer. Over the last 20 years, Dr. Zhang and his team have identified multiple novel cancer markers and oncogenic signaling molecules. Currently, Dr. Zhang is studying how genetic expression, amplification and mutations relate to and regulate each other. Using data from next-generation sequencing, Dr. Zhang is identifying growth-promoting genes of a patient’s cancer.

The new immunotherapy called checkpoint inhibitors—that unleashes the brake on our immune system so it may recognize and fight cancer cells—is successful in some cancers such as melanoma and lung cancer but not in treating the fatal brain cancer, glioblastoma or GBM.   Dr. Rakesh Jain’s research has previously shown that components in and around a tumor such as blood vessels, immune cells, and lack of oxygen can create an immune suppressive tumor microenvironment (TME). His team is focused on combining treatment normalizes a tumor’s abnormal blood vessels (anti-angiogenic) with immune checkpoint inhibitors to enable the inhibitors to effectively fight GBM. If successful, the results of this research will directly inform the design of clinical trials testing their novel treatment strategies to overcome resistance to checkpoint inhibitor immunotherapy.

Dr. Danny Welch and his team have identified eight metastasis suppressor genes that when ‘turned off’ or are ‘abnormal’, allow cancer to spread (metastasize). Research is identifying the minimal parts of the genes necessary that may lead to developing small molecules that ‘mimic’ the gene to suppress metastasis or maintain metastatic tumors in a dormant (inactive) state. They have also identified genetic variabilities in mitochondria — the specialized cell part that makes energy from food — may explain why racial susceptibilities to certain cancers exist and the ability of the cancers to metastasize.  This research could result in a simple blood test that alerts doctors to select treatments likely to succeed for patients at high risk for metastasis and spare those at low risk from unnecessary treatments and associated side effects.

Cancer associated retinopathy (CAR) is a retinal disease of the eye that may occur in patients with various types of cancer. CAR and MAR (melanoma associated retinopathy) are rare syndromes caused by circulating anti-tumor antibodies that cross-react with proteins on healthy retinal cells and cause blindness. Dr. Jean Bennett is a world leader and pioneering physician-scientist in the field of retinal (eye) gene therapy. She developed the first FDA-approved gene therapy for a genetic disease that causes a type of blindness in children. Dr. Bennett is collaborating with Dr. Katherine Uyhazi to pioneer a combination of gene therapy and cell replacement therapy to restore genes and replace damaged cells in the retina by CAR. This groundbreaking research will give hope for restored vision to patients with CAR (small cell lung cancer and those with breast, lung, gynecologic, colon, pancreatic and prostate cancer) and MAR (melanoma).

Dr. Paul Schimmel and Dr. Xiang-Lei Yang are collaborating to develop an innovative immunotherapy to treat metastatic (spreading) cancer. Their research has demonstrated the gene for a vital protein-synthesizing enzyme, SerRS, also has significant anti-cancer and anti-metastasis properties in triple negative breast cancer (TNBC) – one of the most difficult-to-treat breast cancers. SerRS could become a novel cancer treatment by:

• Regulating how cancer cells migrate to nearby healthy cells.
• Stopping blood vessel formation and starving tumors of oxygen and nutrients.
• Activating the immune system to halt metastasis.

Other cancers where SerRS levels correlate with survival and are under the influence of its anti-cancer and anti-metastasis properties include: rectal, esophageal, brain, kidney, lung and thyroid cancer.

Dr. Cesare Spadoni and his team are developing a treatment for rhabdomyosarcoma, the most common pediatric soft tissue sarcoma that results from the fusion of two genes, PAX3 and FOXO1. The small molecule drug, volasertib, is a potent inhibitor of the enzyme PLK1- resulting in reduced activity and stability of the abnormal fused proteins. NFCR translational research funding supports the development of volasertib. The combined treatment of volasertib and chemotherapy vincristine may soon begin a Phase 1 clinical trial to treat rhabdomyosarcoma.

With NFCR translational research funds, Dr. Ronald DePinho and colleagues have developed a promising new drug that inhibits, STAT3, a major signaling protein that is hyperactivated in over 50% of cancers. STAT3 controls networks of genes for numerous cellular processes, including proliferation, survival, angiogenesis, metastasis, invasion, and immune escape. The drug is now in Phase 1 clinical trials to treat various types of advanced cancers.

With long-term support from NFCR and others, Dr. Daniel Haber and his team developed the CTC-iChip – a medical device to capture the few circulating tumor cells (CTCs) present in a standard blood sample from a patient. They developed methods to analyze the genes in CTCs, providing a liquid biopsy and an invaluable window into a patient’s cancer in real time such as the genetic mutations causing resistance to cancer patient’s treatment. The CTC-iChip is currently in use in hospitals worldwide for research purposes. Soon it will be submitted to the FDA for required approval for doctors to obtain the critical information they need for important life-saving treatment decisions for their patients.