NFCR Translational Research: Skin Cancer
New Treatment for Patients with Melanoma in Phase I Clinical Trial
Ronald A. DePinho, M.D. Univ. of Texas MD Anderson Cancer Center, Houston, Texas
STAT3 is a major signaling protein in cells. It is hyperactivated in over 50% of cancers including head and neck cancer. This results in abnormal cell growth, escape from our immune system, metastasis (spreading), and other cancer-associated processes. The development of drugs to target STAT3 effectively has been a challenge for the research community, earning it the label of ‘undruggable’.
Ronald DePinho, M.D. and his colleagues used computer-based drug screening of hundreds of thousands of compounds to identify several candidates that inhibit STAT3 protein when tested in complex tumor models of breast and other various cancers.
NFCR support facilitated the final studies of the most promising inhibitor of STAT3. The new inhibitor drug is treating patients in an ongoing Phase I clinical trial to establish its safety and appropriate dose. Patients with melanoma and other advanced cancers may be eligible to enroll in the trial of this new treatment.
Multi-Action Gene Therapy for Melanoma
Paul B. Fisher, M.Ph., Ph.D. Virginia Commonwealth University, Richmond, VA
NFCR funding since 2008 helped Dr. Paul Fisher think “outside the box” to develop IL/24 gene therapy (IL/24 is from the Interleukin gene family of immune system modulators).
He engineered IL/24 gene to cause 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 to tumors to starve them of vital blood supply, and sensitizes cancer to radiation, chemotherapy and immunotherapy. IL/24 gene therapy is effective in models of melanoma among other cancer types.
Dr. Fisher is translating IL/24 gene therapy to clinical trials to benefit patients. The gene therapy is advancing through pre-clinical research first as a new treatment for fatal brain cancer, GBM (glioblastoma). This would facilitate future trials of IL/24 gene therapy for melanoma patients. IL/24 gene therapy is also effective in models of colon, lung, bladder, liver, pancreas, and prostate cancer, among other types.
Development of New Inhibitor of Cancer Invasion into Healthy Tissue and Metastasis
Paul B. Fisher, M.Ph., Ph.D. Virginia Commonwealth University, Richmond, VA
Invasion of cancer cells into healthy tissue is a hallmark property of cancer. MDA-9/Syntenin is a pro-invasion and pro-metastatic gene discovered by Dr. Paul Fisher with NFCR funds. With leading-edge chemistry and drug design techniques, his team developed the drug, PDZ1i, to inhibit invasion and metastasis properties of MDA-9/Syntenin. PDZ1i shows profound “anti-invasive” and “anti-metastatic” activity in models of melanoma and liver, lung, brain, pancreas, breast and prostate cancer and neuroblastoma. PDZ1i works well with chemotherapy, radiation, or immunotherapy to kill cancer cells. Patients with hepatocellular cancer (HCC)—the main type of liver cancer, need effective treatments to save their lives. NFCR funds are advancing the required pre-clinical research of PDZ1i to apply for the IND (Investigational New Drug) application and gain FDA approval for a Phase 1 clinical trial for HCC patients. Success in the trial for HCC patients will facilitate future trials of PDZ1i treatment for melanoma and other types of cancer.
BASIC RESEARCH PROJECTS
Dr. Danny Welch and his team discovered eight genes that may get turned off or become abnormal as cancer cells become metastatic cells – called metastasis suppressor genes. KISS1 gene was discovered in melanoma and the scientists determined that the cells expressing KISS1 can complete all of the early steps of the metastatic process but do not form a new metastatic site. The Welch lab continues to define the significant parts of the KISS1 gene to develop small anti-metastasis therapeutics that mimic the KISS1 gene’s function and arrest cells in forming a new metastatic lesion.
Dr. Wei Zhang pioneered a new high-tech single‐cell RNA sequencing methodology at his university, Wake Forest Baptist Comprehensive Cancer Center on 4 patient lung tumor samples. This facilitated a high‐resolution study of the tumor‐immune cell microenvironment. Subsequently, over 40 samples from lung, endometrial, and melanoma patients have been analyzed with a goal to elucidate tumor and immune response states relating to factors including tumor mutation status, patient race and smoking history, and immunotherapy treatment responses. Dr. Zhang is conducting important research studies to advance Precision Oncology with the ultimate goal of maximizing outcomes for every cancer patient.
