NFCR Basic Research in Action: Metastasis

Metastatic cancer is the term used to describe any cancer that has spread from the area it started in to other areas of the body. For some types of cancer, metastasis is also called stage IV cancer, and metastatic cancers are often hard to control.

Cancer can spread to any part of the body, but the most common sites of metastasis are the bones, brain, liver and lungs. Metastatic cancer is the reason why 90% of cancer patients lose their battle. However, metastasis research receives less than 5% of research funding from most organizations.

Development of anti-metastatic drugs has lagged because distinctive characteristics of metastases (as opposed to simply being cancer cells) have not been as easy to identify.

Dr. Danny Welch  is a pioneer and leader in this complex research field. He has a two-pronged approach to understand how metastasis develops and create novel strategies to save patient’s lives. His team discovered eight of the more than 30 known metastasis suppressor genes that when ‘turned off’ or are ‘abnormal’, allow cancer to metastasize.

Further research based on these discoveries may lead to the design of molecules that either prevent metastasis from happening or maintain metastatic tumors in a dormant (inactive state.)

The Welch lab discovered DNA variabilities in mitochondria — the specialized cell part that makes energy from food — may explain racial susceptibilities to certain cancers and the ability of the cancers to metastasize. Recently, the scientists identified specific changes in an important protein builder in mitochondria, which may explain these biological changes. 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 low risk patients unnecessary treatments with associated side effects.

The collaborative team of Dr. Paul Schimmel and Dr. Xiang-Lei Yang focuses on  SerRS, one member of the aminoacyl-tRNA synthetases, a family of enzymes involved in the first step of protein synthesis in all living things. In addition to this vital role, they found that SerRS regulates metastatic-related cellular processes. Their research demonstrates SerRS is a potent suppressor of cancer progression and metastasis and may activate the immune system to fight cancer.

Their research focuses on 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 (one of the first steps in metastasis).
• Stopping blood vessel formation and starving tumors of oxygen and nutrients.
• Activating the immune system to halt metastasis.

Research indicates SerRS levels also correlate with survival and influences its anti-cancer and anti-metastasis properties in rectal, esophageal, brain, kidney, lung and thyroid cancer. This critical area of research may lead to novel therapeutic applications.

Dr. Wei Zhang pursues cutting-edge molecular profiling technologies and develops bioinformatics tools to investigate better the underlying mechanisms of cancer initiation and cancer progression as it worsens and spreads. Through detailed analysis of activities of individual cells composing the tumor microenvironment, his team can model the relationship of tumor cell genomics to the mechanisms driving tumor progression and make predictions for treatment responses or resistance with the overall goal of better outcomes for cancer patients in the future.

Dr. Ronald DePinho and his colleagues used computer-based drug screening of hundreds of thousands of compounds to identify several candidates that inhibit STAT3 protein, a major signaling protein in cells is hyperactivated in over 50% of cancers.  STAT3 when hyperactived causes abnormal cell growth, escape from our immune system, metastasis (spreading), and other cancer-associated processes. NFCR support facilitated the final studies of the most promising inhibitor of STAT3. An ongoing Phase I clinical trial is establishing its safety and appropriate dose. Patients with advanced cancer may be eligible to enroll in the trial of this new treatment.

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.

Dr. Paul Fisher is developing IL/24 gene therapy (IL/24 is from the Interleukin gene family of immune system modulators). He engineered IL/24 gene to reach cancer cells — at all sites in the body — to commit suicide (normal way cells die). Healthy cells are unaffected by IL/24 gene’s effects. IL/24 gene modulates the immune system to kill cancer, inhibits blood vessel formation (anti-angiogenesis) to tumors to starve them of vital blood supply, and sensitizes cancer to radiation, chemotherapy and immunotherapy. With NFCR translational funding, IL/24 gene therapy is advancing through pre-clinical research first as a new treatment for fatal brain cancer, GBM (glioblastoma). IL/24 gene therapy is effective in models of numerous types of advanced cancer: melanoma and colon, lung, bladder, prostate, liver, and pancreatic cancer, among other types.