Research Collaboration Award
Memphis, TN, July 13, 2015 -- The Hartwell Foundation officially announced the winners of a Biomedical Research Collaboration Award to Neal M. Alto, Ph.D., 2011 Hartwell Investigator and Associate Professor, Department of Microbiology, University of Texas Southwestern Medical Center and Noriko Satake, MD, 2011 Hartwell Investigator and Associate Professor, Department of Pediatrics, University of California, Davis, for their proposal “Targeted Cancer Therapy: Novel Antibody-Toxin Conjugates”. The researchers will receive $699,358 in combined direct cost over three years. Both UT Southwestern and UC Davis are current Hartwell Centers of Biomedical Research Excellence.
Each year over 12,000 children in the US receive the diagnosis of cancer. Two of the most common forms in children are B-cell malignancy (leukemia or lymphoma commonly arise in white blood cells from bone marrow and lymph nodes) and neuroblastoma (most commonly arises in and around the adrenal glands that sit atop the kidneys). About a third of all affected patients fall into a high-risk category, where treatments of choice have limited efficacy and survival rates are often less than 30%.
The standard of care in most cancers is to kill or control cancer growth by systemic delivery of potent drugs or chemicals. Unfortunately, chemotherapeutics are often associated with side effects that include nausea, fatigue, flu-like symptoms, anemia and severe pain, and which may in children cause a delay in maturation, contribute to slow physical growth and damage vital developing organs. Side effects occur because chemotherapy indiscriminately affects common biological pathways found in both cancer and normal cells.
To overcome the unmet need for an effective and safe cancer therapy for children, Alto and Satake propose to develop a targeted approach to kill cancer that will, by virtue of the specificity of their innovative drug-delivery platform, eliminate or substantially minimize toxic side-effects. Their collaboration will leverage a new class of biopharmaceutical drugs developed in the Alto laboratory called toxins, which by their selection can be highly specific in killing certain cancer cells, together with innovative cell-targeting antibody technology from the Satake laboratory, which will provide effective drug delivery specifically to the cancer.
Neal Alto, a research scientist in microbiology, was a Hartwell Investigator in 2011 for his proposal on “Discovery of Cancer Inhibition Pathways by Novel Bacterial Toxins and Effector Proteins.” His early-stage approach was to develop novel therapeutic agents derived from bacteria that have the ability to kill specific kinds of cancer cells. He proposed to identify the unique relationship between the killing action of the toxins with those genes involved in abnormal cellular growth (oncogenes) and those that naturally protect cells from the path to cancer (tumor suppressor genes). His achievements were to successfully develop a library of over 200 bacterial toxins, together with a high-throughput assay platform, useful for cancer therapeutic discovery. He has moved several of the bacterial toxins into pre-clinical mouse models for non-small cell lung cancer.
Noriko Satake, a pediatric oncologist and clinical research scientist, was a 2011 Hartwell Investigator for her proposal on the “Targeted Therapy for Childhood Acute Lymphoblastic Leukemia: Silencing the Mxd3 Gene Using Small Interfering RNA.” She developed an effective antibody-conjugate drug delivery system against B-cell leukemia/lymphoma. The active conjugate included antisense DNA that targets the transcription factor MXD3 in B-cell type ALL and a humanized antibody that binds specifically to B cells. The conjugate had significant therapeutic efficacy in xenograft mouse models using a human leukemia cell line, as well as in primary clinical samples. Her achievement was to successfully demonstrate that under the right conditions antibodies attached to a cancer-killing drug will deliver small molecule inhibitors specifically and efficaciously to cancer cells, providing support for the development of a new approach to targeted therapy for leukemia.
The Alto and Satake inter-institutional collaboration brings together the skills and tools to identify novel bacterial toxins that kill cancer cells; manufacturing technology for antibody-toxin conjugates; and a human cancer animal model to test the novel antibody-toxin conjugates for efficacy and their mechanism of action. By leveraging the focus of the UT Southwestern Department of Microbiology on mechanisms underlying host-pathogen interactions with the UC Davis Non-Human Primate center for animal models of disease and safety, together with the UC Davis Good Manufacturing Practice (GMP) facility for the manufacture of clinical grade drugs, their collaboration positions them uniquely for “bench-to-bedside” translation of targeted cancer therapy.
If successful, the Alto-Satake collaboration will advance childhood cancer therapy by reducing or eliminating the devastating off-target side effects observed in current chemotherapy, improving not only the quality of life in affected children but their survival, as well.
“The collaboration between Alto and Satake will represent a major step toward moving their therapeutic discoveries to clinical trials,” said Fred Dombrose, President of The Hartwell Foundation. “Discovery of the cellular mechanism of action of the antibody-toxin conjugates in killing cancer has the potential to identify more targets and more advanced therapies, including translation to the clinic for other diseases, as well.”
Fostering collaborations between investigators of complementary scientific strengths is one of the objectives of The Hartwell Foundation in its mission to fund innovative, early-stage applied biomedical research with the potential to benefit children of the United States.
For additional information see www.thehartwellfoundation.org