| 2011 — 2015 |
Rebhun, Robert B |
K01Activity Code Description:
For support of a scientist, committed to research, in need of both advanced research training and additional experience. |
The Relationship Between Epidermal Growth Factor Receptor and Hedgehog Signaling @ University of California At Davis
DESCRIPTION (provided by applicant): It is estimated that over 140,000 people in the United States will be diagnosed with cancer of the colon and rectum and approximately 51,000 deaths will occur from this disease in 2010. The majority of colon cancer-related deaths can be attributed to metastasis. Therefore, a better understanding of the metastatic process may lead to prognostic and therapeutic advancements. Epidermal growth factor receptor (EGF-R) and Hedgehog (Hh) signaling pathways are independently known to contribute to the development or progression of many cancers including malignancies of the skin, brain, lung, breast, prostate, pancreas, ovary, and colon. Several studies now support the notion that bi- directional cross-talk between Hh and EGF-R can dramatically alter the cellular effects of either pathway alone. However, the implication of these complex interactions in regard to the development, progression, prognosis, and treatment of cancer remain largely unexplored. The goal of this research plan is to determine the contribution of EGF-R and Hh signaling interactions to the progression and metastasis of human colon cancer cells. The specific aims are to 1) Determine the effects of EGF-R on Hh mediated colon cancer cell signaling, growth, and survival, and to 2) Determine how EGF-R and Hh signaling modulates growth, survival, and spontaneous metastasis of human colon cancer cells growing orthotopically in mice. The K01 award would support Dr. Rebhun's career development and will further prepare him for an independent research career in comparative and translational cancer research. Dr. Rebhun is a board certified clinical veterinary oncologist (DVM, Diplomate ACVIM-Oncology) and is a dual-trained clinician/scientist with a Ph.D. degree in cancer biology. Five years of mentored support is requested. PUBLIC HEALTH RELEVANCE (provided by applicant): Colon cancer is the third most common cause of cancer related death in both men and women and it is estimated that over 50,000 people will die of this disease within the United States in 2010. A better understanding of colon cancer cell signaling and metastasis is required in order to advance treatment of this disease. The goal of this project is to understand and describe interactions between specific cell signaling pathways that have individually been implicated in the progression of colon cancer.
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0.948 |
| 2017 — 2021 |
Canter, Robert J
Rebhun, Robert B |
U01Activity Code Description:
To support a discrete, specified, circumscribed project to be performed by the named investigator(s) in an area representing his or her specific interest and competencies. |
Enhancing Natural Killer Immunotherapy With First-in-Dog Trials of Inhaled Recombit Il-15 and Super-Agonist Il-15 in Naturally Occurring Canine Cancers @ University of California At Davis
Project Summary This proposal seeks to build on our extensive preliminary data in canine immunotherapy trials to demonstrate that novel methods of exogenous cytokine delivery in combination with autologous natural killer (NK) cells in first-in-dog clinical trials represents a potentially high impact approach to optimize non-T cell based immunotherapies. This work is targeted to dogs with typically lethal, naturally occurring osteosarcoma (OSA) and melanoma, and the findings are expected to have important relevance for the design and translation of innovative immunotherapy approaches in humans. Inhaled (IH) IL-15 offers the advantages of local delivery of this immune-stimulatory cytokine, while limiting systemic exposure and thus potential toxicity. Super-agonist IL- 15 offers increased half-life and greater anti-tumor effects. Therefore, each of these cytokines is anticipated to alter the risk/benefit ratio in favor of their use. To accomplish these objectives, we propose the following three specific aims: 1) Targeting gross pulmonary metastases (OSA and melanoma) with first-in-dog delivery of inhaled (IH) human IL-15 and super-agonist IL-15; 2) Phase II trial of IH IL-15 and autologous NK cells to treat gross OSA and melanoma pulmonary metastases, and; 3) Targeting micro-metastatic disease using super- agonist IL-15 in primary OSA. The canine model represents a powerful tool in cancer immunotherapy research as an important link between murine models and human clinical studies. Dogs represent an attractive outbred combination of companion animals that experience spontaneous cancer development in the setting of an intact immune system. Importantly, these studies are designed to evaluate novel treatment combinations for advanced pulmonary metastases in the setting of gross disease, but also will determine the impact of this approach as first-line therapy when combined with standard-of-care treatments. Moreover, this work seeks to elucidate the cellular and molecular mechanisms that mediate an anti-tumor response (or non-response) in dogs with naturally occurring cancers. We will have the unique opportunity to perform whole exome sequencing and RNASeq on tumor tissue pre- and post-immunotherapy, and we will investigate whether a signature of mutational landscape and gene expression profiles can be developed to prospectively predict outcome and response to immune therapies. We will correlate these data to immunohistochemical, flow cytometry, and serum cytokine readouts for evidence of transition from ?cold? to ?hot? tumors predictive of favorable long term outcome. Hence, these canine trials and bio-marker studies represent an ideal strategy to inform and facilitate the rapid translation of novel, potentially high impact immune therapies to human patients with aggressive cancers.
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0.948 |