NFCR Translational Research: Breast Cancer
New Treatment for Patients with Advanced Breast 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. Hyperactivation of STAT3 occurs in over 50% of cancers including breast cancer, resulting 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 treatment is now treating patients in an ongoing Phase I clinical trial to establish its safety and appropriate dose. Patients with advanced breast cancer and other advanced cancers may be eligible to enroll in the trial of this new treatment.
Molecular Imaging Detects Cancer-free Margins During Breast Cancer Lumpectomies
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. For example, in 25% of lumpectomies, breast cancer patients must return later for a second surgery.
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. Light-emitting probes are being developed for colon, prostate, and lung cancer to benefit numerous patients during their surgery.
MULTI-ACTION GENE THERAPY FOR METASTATIC CANCERS
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 metastatic breast 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 gene therapy for breast cancer patients. IL/24 gene therapy is also effective in models of melanoma and colon, lung, bladder, liver, pancreas, and prostate cancer, among other types.
Innovative Platform: Efficient Development of Multi-functional Antibodies
Pär Nordlund, Ph.D. Karolinska institute, Solna, Sweden
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 the new multi-functional antibodies to clinical trials to reach patients. The first approach will focus on tumors with immuno-suppressed microenvironment such as triple-negative breast cancer and non-small cell lung cancer. NFCR translational funding is accelerating the completion of the required pre-clinical research.
BASIC RESEARCH PROJECTS
Dr. Daniel Haber is using his team’s advanced micro-engineered device to capture the rare CTCs among billions of normal cells in a standard blood sample. The researchers are using the CRISPR gene-editing tool on the captured bresat CTCs to identify genes allowing tumor cells to ‘rest’ and ‘reawake’. Ultimately, therapies may be developed to suppress the genes, giving women greater hope for surviving the recurrence of breast cancer.
Dr. Paul Schimmel and Dr. Xiang-Lei Yang, experts in the protein synthesizing enzymes Aminoacyl-tRNA synthetases (aaRS), also study the enzyme’s other unexpected roles. One aaRS, SerRS, thwarts cancer’s growth and may activate the immune system. SerRS may also be a suppressor of metastasis as enzyme levels are significantly decreased in breast tissue during metastasis. Their research may lead to a novel way to treat women with triple negative breast cancer, offering them hope that their cancer can be effectively treated.
Dr. Danny Welch and his team are exploring how mitochondria – a specialized cell part that generates energy for our bodies – may determine why breast cancer metastases develop in some patients, but not in others. Differences in tumor formation, metastasis location and responses to therapy could be from our mitochondrial DNA. This research may lead to a simple blood test to guide doctors in treating patients who are susceptible to metastasis and may need more aggressive treatment, or spare other patients of unnecessary harsh side effects.
Dr. Welch’s team also discovered eight genes that get turned off in cancer, as the cells become metastatic. This research can lead to unique anti-metastasis therapeutics such as smaller proteins that ‘mimic’ the function of the active part of the turned-off gene and may arrest breast cancer metastasis.
