NFCR Translational Research: Lung Cancer
New Treatment for Patients with Advanced Lung Cancer 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 lung 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 advanced lung cancer and other advanced cancers may be eligible to enroll in the trial of this new treatment.
Novel Antibody Treatment Under Development for Non-Small Cell Lung Cancer
Daniel D. Von Hoff, M.D., FACP Translational Genomics Research Institute, Phoenix, AZ
Dr. Daniel Von Hoff, a pioneer and world leading physician-scientist in translational medicine, has personally been involved in over 200 clinical trials. In 1985, began his continuous support from NFCR that led to gemcitabine, the first approved treatment for pancreatic cancer.
A new current focus is developing monoclonal antibodies to treat metastatic (spreading) colon cancer that is refractory to other standard treatments. A novel antibody targets a key protein on colon cancer cells involved in cancer spread and progression. Promising results have been demonstrated in colon cancer models.
NFCR funds are facilitating the required pre-clinical studies to translate the antibody into clinical development as a new treatment for metastatic colon cancer that no longer responds to standard therapy.
New Treatment for Small-Cell Lung Cancer Under Development
Michael B. Sporn, M.D. formerly of Geisel School of Medicine at Dartmouth, Hanover, NH
Fenretinide, a drug similar in structure to Vitamin A, may offer patients a life-saving treatment. Previously, former NFCR-funded scientist, Dr. Michael Sporn, researched fenretinide and proved its safety in humans for other cancers. Subsequently, the drug demonstrated safety and effectiveness in patients. Fenretinide is toxic to cancer cells by activating the cell suicide pathway (apoptosis). Scientists discovered fenretinide reactivates the immune system to complement apoptosis and it is effective in small-cell lung cancer models. NFCR’s support helped develop a unique delivery system for fenretinide and gain FDA approval to treat non-Hodgkin T-cell Lymphoma patients who no longer respond to their current therapy. Enrollment in the Phase 1 trial will begin soon. Success in clinical trials for non-Hodgkin T-cell lymphoma will facilitate a trial to treat small-cell lung cancer with fenretinide.
Pre-clinical Development of Multi-Action Gene Therapy for Metastatic Lung Cancer
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 a vital blood supply, and sensitizes cancer to radiation, chemotherapy and immunotherapy. IL/24 gene therapy is effective in models of metastatic lung cancer among other cancer types.
Dr. Fisher is bringing 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 for lung cancer patients. IL/24 gene therapy is also effective in models of melanoma and colon, breast, 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. He is developing PDZ1i for clinical trials. PDZ1i shows profound “anti-invasive” and “anti-metastatic” activity in models of liver, lung, brain, pancreas, breast and prostate cancer and melanoma 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 lung and other types of cancer.
Molecular Imaging Detects Cancer-free Margins During Surgery
James P. Basilion, Ph.D. Case Western Reserve Univ. Cleveland, OH
The best chance of a cure for many early-stage cancers is complete, surgical resection. A challenge for surgeons is determining where cancer ends, and healthy tissue begins – known as ‘cancer margins’. Immediate margin detection can benefit many patients who otherwise must return for a second surgery after pathology lab results of surgery samples determine margins were not cancer-free. With NFCR funding since 2005, Dr. James Basilion developed molecular imaging light-emitting probes to bind only cancer cells. Surgeons quickly apply the probe and a camera visualizes any remaining cancer cells to be resected or the margins of the surgery are ‘cancer-free’.
Dr. Basilion is translating the molecular imaging probes into the clinics. With NFCR funding, the probe is being optimized in pre-clinical studies for detection of margins in breast cancer lumpectomies. After approval of the Initial New Drug (IND) from the FDA, the probe will enter Phase I clinical trials to improve cure rates for breast cancer. Under development are light-emitting probes to detect cancer margins in lung cancer. Successful clinical trials of the probe for breast cancer will facilitate a future trial to benefit lung cancer patients.
Innovative Platform: Efficient Development of Multi-functional Antibodies
A new multi-targeted approach is being developed to direct drugs to specific cell types; localize drugs to the tumor or tumor microenvironment; bring immune cells to the tumor; overcome resistance; and reduce side effects by a more targeted effect. Prof. Pär Nordlund and his team developed an innovative platform using their modular and combinatorial approach to efficiently make hundreds of prototype multi-functional antibodies in parallel and undergo pre-clinical tests. This rapid identification of optimal candidates minimizes risks in clinical trials, surpassing the standard comprehensive protein engineering effort that leads to only a few therapies in pre-clinical studies and long development cycles before translation reaches patients in the clinical stages. The scientists are bringing new multi-functional antibodies to clinical trials and reach patients. The first approach focus on tumors with immuno-suppressed microenvironment including non-small cell lung cancer and triple-negative breast cancer. NFCR translational funding is accelerating the completion of the required pre-clinical research.
