Area:
Cell Biology, Oncology, Pharmacology
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High-probability grants
According to our matching algorithm, Steffan T. Nawrocki is the likely recipient of the following grants.
Years |
Recipients |
Code |
Title / Keywords |
Matching score |
2014 — 2015 |
Nawrocki, Steffan T |
R21Activity Code Description: To encourage the development of new research activities in categorical program areas. (Support generally is restricted in level of support and in time.) |
Disrupting Brain Metastogenesis in Breast Cancer @ University of Texas Hlth Science Center
DESCRIPTION (provided by applicant): Women with breast cancer who develop brain metastases have a dismal prognosis and very few achieve long- term survival. Clinical outcomes for these patients have not significantly improved over the last several decades for a number of reasons including the poor penetration of most anticancer drugs across the blood- brain barrier, the specific exclusion of patients with brain metastases from the vast majority of clinical trials of experimental therapeutic agents, and an incomplete understanding of the biochemical and molecular events that are involved in the metastasis of primary breast tumors to the brain. Autophagy is an evolutionarily conserved lysosomal system of protein degradation that is utilized for the turnover of long-lived proteins and organelles. A number of recent studies have shown that autophagy plays an important role in cancer pathogenesis as it can function to provide a source of metabolic fuel to maintain cell survival under stressful conditions including those triggered by hypoxia and anticancer therapy. We and others have shown that autophagy significantly contributes to drug resistance and accordingly, that inhibiting this degradation pathway significantly augments the efficacy of multiple classes of cancer therapeutics and interferes with disease progression. However, the mechanistic basis for this has not been fully elucidated and the specific role that autophagy plays in the regulation of breast cancer metastasis nor its significance as a target for the prevention and therapy of metastatic disease has not been rigorously investigated. Our preliminary data indicate that a functional autophagy pathway may be required for primary breast tumors to metastasize to the brain, suggesting that targeting autophagy may be an effective approach to prevent and treat metastatic brain tumors. We recently discovered a novel inhibitor of autophagy that readily crosses the blood-brain barrier, has significant anti-neoplastic activity, and is therefore a very promising new candidate drug for the treatment of both primary and metastatic breast tumors. We hypothesize that genetic or pharmacological inhibition of autophagy will antagonize breast cancer progression, disrupt the establishment of metastatic tumors in the brain, and significantly augment the efficacy of the small molecule EGFR/HER2 inhibitor lapatinib. In Aim 1, we will investigate the specific roles that autophagy plays in the development and progression of primary and metastatic breast tumors. In Aim 2, we will determine the mechanism(s) by which autophagy inhibition enhances the anti-brain metastatic activity of lapatinib for the treatment of breast cancer. At the conclusion of these studies, we will have significantly expanded our knowledge regarding the role of autophagy in breast cancer pathogenesis and will have generated critical new information required to develop novel strategies to optimally target brain metastases for the treatment of breast cancer and other malignancies.
|
0.964 |
2015 — 2020 |
Nawrocki, Steffan T |
R01Activity 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. |
Endoplasmic Reticulum Stress and Oncoviral Therapy
? DESCRIPTION (provided by applicant): Activation of the oncogene MYC is a frequent event in multiple myeloma (MM) that contributes to refractory/high-risk disease and is therefore an attractive therapeutic target. We previously demonstrated that a novel reovirus formulation for cancer therapy called Reolysin is a promising new agent for patients with MM as it exhibits significant activity in cell lines, primary patient cells, and mouse models of the disease. However, the mechanisms that mediate reovirus sensitivity in MM cells are not well understood. Our preliminary data indicate that Reolysin may be particularly effective for MM patients with high MYC activity and/or those that are refractory to bortezomib as these cells exhibit hypersensitivity to Reolysin-induced cell death. We hypothesize that constitutive MYC activity renders refractory/high-risk MM cells uniquely sensitive to Reolysin through an endoplasmic reticulum (ER) stress-mediated mechanism. In Aim 1, we will determine the role of MYC as a regulator of Reolysin sensitivity. A potential link between MYC, PKR activity, and ER stress will be evaluated. In Aim 2, we will investigate the mechanisms by which the evolution of acquired bortezomib resistance confers increased sensitivity to Reolysin. Finally, in Aim 3 we will determine the role of ER stress-induced autophagy as a regulator of Reolysin-mediated cell death. At the conclusion of these studies, we will have significantly expanded our knowledge regarding the mechanisms that promote improved reovirus efficacy in relapsed/high- risk MM cells and will have generated critical new information required to optimally utilize Reolysin for the treatment of advanced and drug-refractory MM.
|
0.964 |