NFCR Basic Research in Action: Genomics Research

Genomics – in general – is the study of a complete set of genetic material (DNA), and when it comes to cancer research, studying DNA is crucial. Cancer develops when DNA becomes damaged or changed. Some cancer-causing genetic changes are inherited.  Genetic changes can also arise during a person’s lifetime as a result of errors that occur as cells divide or because of damage to DNA caused by exposure to certain environmental factors. These may include exposure to chemicals (such as those in cigarette smoke), radiation, certain microbes, ultraviolet rays or other environmental factors. Studying cancer genomics involves exploring the differences between cancer cells and normal cells.

There’s a paradigm shift taking place: We’re moving from an organ-focused (type of cancer) approach to a gene-focused approach. This shift is already having a profound effect on the way cancer is treated and allows doctors to provide more individualized options for patients (also known as precision medicine or precision oncology).

In addition to the specific projects listed below, genomics research is part of the work being conducted by every scientist NFCR funds. For many years, NFCR has distinguished itself from other organizations by emphasizing long-term, transformative research and working to move people toward cancer genomics.

One of the most fundamental questions facing scientists today is how seemingly normal cells become cancerous. To better understand how this happens, Dr. Paul Schimmel has dedicated more than 40 years to examining the minute forms and intricate functions of molecular biology. In 1983, Dr. Schimmel developed the concept for what are now known as ESTs (expressed sequence tags) and the strategy of shotgun sequencing. These approaches were later adopted in the human genome project. In fact, his work on the development of ESTs is known as one of the four key developments that launched the human genome project.

Dr. Xiang-Lei Yang’s research, in collaboration with Dr. Paul Schimmel, combines the leading-edge multidisciplinary approaches of biophysics, biochemistry, cell biology and structural analysis. They have 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. SerRS could serve as a biomarker to guide selection for clinical trials.

Dr. Wei Zhang has devoted his entire career to identifying key molecular and genomic events that drive the development and progression of cancer. His research addresses the variability in cell properties, within and across cancer types, which often leads to treatment resistance and poor survival in patients. Recent highlights from his lab include:

• Discovery of a second gene mutation combined with a cancer-causing gene in lung cancer serves as a marker of poor survival.
• Targeting metabolism in lung cells may improve immunotherapy in African American patients.
• Piloting a new technique to map protein expression to specific location in cells will help develop more effective therapeutics.

Dr. Zhang’s research will impact patients with non-Hodgkin’s lymphoma, leukemia, melanoma, and lung, gastrointestinal, pancreatic, ovarian, uterine, brain and liver cancer.

Dr. Danny Welch is a leader and pioneer in metastatic or spreading cancer. Metastatic cancer is the reason why 90% of cancer patients lose their battle. 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. Welch’s team has identified eight metastasis suppressor genes that when ‘turned off’ or are ‘abnormal’, allow cancer to 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.

Dr. Daniel Haber is a renowned leader on genetic abnormalities of cancer – from inherited mutations (with familial predisposition) to mutations that are acquired by tumors themselves. With NFCR funding since 2000, his research aims to guide targeted drug therapies. Dr. 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 in real-time to define genetic mutations causing resistance to cancer patient’s treatment and guide the use of immunotherapy and other treatments.  The CTC-iChip is currently in use in hospitals worldwide for research purpose. In the near future, the technology will be submitted to the FDA for required approval. Doctors can then use the CTC-iChip to obtain the critical information they need for important treatment decisions.

Dr. Paul Fisher has developed innovative approaches for identifying genes of relevance in the carcinogenic process and created effective gene-based therapies for cancer, which are being translated into the clinic with promising early results. His laboratory has pioneered innovative genomic approaches, including rapid subtraction hybridization, reciprocal subtraction differential RNA display, and overlapping pathway screening, culminating in the identification of novel genes involved in cancer cell growth and cell cycle control, and apoptosis (cell suicide).

Dr. Ronald DePinho’s research takes an integrated genomics and biological systems approach to several areas of focus: oncogenes (cancer-causing genes) and tumor suppressor genes; mechanisms driving telomeres (end part of chromosomes) and DNA damage; the role of cancer/stem cells and related developmental pathways in tumors; development of mouse models of human cancers; discovery of novel cancer therapies. His team developed an inhibitor to STAT3 gene which is hyperactivated in more than 40% of cancers and controls networks of genes for multiple cellular processes, including proliferation, survival, angiogenesis, metastasis, invasion, and immune escape. The inhibitor is currently in clinical trials treating numerous types of advanced cancer.