The Basic-Clinical Partnerships Research Grant program at the University of Arizona Cancer Center, currently led by Marty Pagel, PhD, supports collaborative translational research pilot projects. This funding mechanism, supported by the UA Cancer Center Support Grant (number CA023074), is designed to promote translational research projects that are led by both a basic scientist and a clinician.
Grant recipients were chosen by a scientific review committee comprised of University of Arizona faculty, and the grant distribution for 2013 and 2014 will fund six teams of investigators for a total of $241,000. Funded topics include breast cancer, ovarian cancer, brain cancer, myeloma bone disease, and lymphoma. The researchers and their projects are:
Pavani Chalasani, MD, MPH, Assistant Professor of Medicine, and Amanda Baker, PharmD, PhD, Research Associate Professor of Medicine and Director. "A single arm Phase II trial to assess association of low BRCA1 protein expression with overall response rate in patients with metastatic breast cancer treated with pegylated liposomal doxorubicin" - Sporadic “BRCAness” may have therapeutic implications, as a predictor for increased sensitivity to DNA damaging agents. There is recent literature suggesting relative resistance of tumors with low BRCA1 protein to agents which act by stabilizing microtubule polymers. If these hypotheses are true, one could propose precision medicine by determining tumor BRCA1 protein expression as a predictive marker for response to different classes of chemotherapy agents. This would potentially optimize patient outcomes, avoid the unwarranted toxicity of chemotherapeutic agents destined to fail quickly, and decrease economic burden to the patient and society. This study is a prospective single arm phase II trial to assess the association of BRCA1 protein expression in the primary tumor with overall response rate in patients with metastatic breast cancer treated with pegylated liposomal doxorubicin. Results of this proposed project can easily form the foundation for a future confirmatory multi-institutional prospective trial.
Guang Yao, PhD, Assistant Professor of Molecular and Cellular Biology, and Wenxin Zheng, MD, Professor of Pathology. "Molecular mechanism of tubal secretory cell expansion and biomarkers for ovarian cancer early detection" - Also supported with research funds from Better Than Ever. Women’s pelvic serous cancer constitutes serous carcinomas of the ovary, fallopian tube and peritoneum. It is now known that the majority of women’s pelvic serous cancers are derived from fallopian tubal epithelial cells. Such understanding has gradually shifted the research focus from the ovary or the ovarian surface epithelia to the tubal epithelial cells. Two different types of epithelial cells are present in tubal mucosa: secretory and ciliated cells. The overgrowth of tubal secretory cells serves as a latent precancer or a common pathway prior to the development into ovarian serous cancer of either low-grade or high-grade. We aim to find the basic cellular and molecular mechanisms leading to the secretory cell expansion (SCE) within the fallopian tubal mucosa, and to apply the mechanistic understanding of tubal SCE for developing early detection markers of ovarian serous cancers.
Jonathan Schatz, MD, Assistant Professor of Medicine, and Soham Puvvada, MD, Assistant Professor of Clinical Medicine. "Cyclin-dependent kinase inhibition as a synthetic lethal approach in high-risk diffuse Large B-Cell Lymphoma with co-expression of c-MYC and BCL2" - Diffuse large B-cell lymphoma (DLBCL) cases that co-express c-MYC and BCL2 have poor prognosis, with five-year overall survival of less than 40 percent, compared with 70 percent in cases that are not double-positive. Development of better therapies requires drugs targeting specific processes necessary for the survival of these tumors. Our preliminary data show a connection between c-MYC expression and increased activity of the cyclin-dependent kinases in double-positive DLBCL. This study will lay the groundwork for evaluation of dinaciclib and similar-drugs in double-positive DLBCL, patients by defining mechanisms and biomarkers of efficacy. The approach, primary investigators, and collaborative environment will permit rapid translation of findings into an investigator-initiated clinical trial of dinaciclib at the UACC during the period of grant funding.
Eric Weterings, PhD, Assistant Professor of Radiation Oncology, and Baldassarre Stea, MD, PhD, Professor and Department Head of Radiation Oncology. "A novel radiation-sensitizing agent for treatment of glioblastoma multiforme (GBM)" - Glioblastoma multiforme (GBM) is the most common and aggressive form of primary brain cancers. Radiation therapy with Temozolamide is the standard of care after resection. However, GBM tumors typically infiltrate the surrounding healthy brain tissue, which limits the ability of radiation treatment to eradicate the disease as increasing doses of radiation increases the likelihood of collateral damage to the normal tissue. In addition, GBM tumors are highly radiation refractory, in part due to an elevated expression of enzymes that are capable of repairing radiation-induced DNA double strand breaks. For these reasons, the availability of a radiation-sensitizing drug which exerts its action by suppressing DNA break repair is likely to improve the outcome of GBM patients treated with radiotherapy. We have previously shown in our laboratory that the chemotherapeutic drug 5-azacytidine is capable of suppressing DNA break repair and markedly sensitizing prostate tumors to radiation therapy. Based on this foundation and on the fact that 5-azacytidine readily crosses the blood-brain barrier, we hypothesize that 5-azacytidine could be a potential radiation-sensitizing drug for GBM tumors as well. In order to evaluate this hypothesis, we plan on measuring the extent to which radiation-sensitization occurs in a battery of human-derived GBM cell lines and tumors after treatment with 5-azacytidine. If successful, these studies could form a solid proof-of-principle for the applicability of 5-azacytidine in GBM treatment and could form the basis for a clinical trial in this devastating disease.
Terry Landowski, PhD, Associate Professor of Medicine, and Amit Agarwal, MD, PhD, Assistant Professor of Medicine (as of July 1). "A novel non-cytotoxic approach for the treatment of myeloma bone disease" - Multiple myeloma affects more than 20,000 individuals each year and remains incurable in a vast majority of these patients. Multiple myeloma and other bone resident tumors occupy the endosteal niche, where they usurp features of hematopoietic stem cells (HSCs). The objective of this proposal is to develop a non‐cytotoxic strategy for the treatment of myeloma bone disease. We propose that alpha6 integrin is needed for myeloma bone marrow localization and that myeloma cells require alpha6 integrin cleavage for tumor progression and dissemination. The work will provide important understanding of the functions of integrin/ECM interactions in the stem cell niche, and reveal critically needed approaches for management of debilitating bone disease.
John JB Allen, PhD, Distinguished Professor of Clinical Psychology, Cognitive Science and Neuroscience, and Karen Weihs, MD, Associate Professor of Psychiatry. "Autonomic physiology of emotion regulation and depression in breast cancer survivorship" - This study will examine whether a physiological index of emotion regulation – cardiac vagal control – can enhance the prediction of depression in women with breast cancer. This is a significant public health problem, in particular given the nearly double rate of depression in breast cancer as compared to community controls and the deleterious impact of depression on functional and health outcomes when emerging in the context of breast cancer. Cardiac vagal control reflects parasympathetic nervous system activity. This system serves to calm and restore the body, and greater activity in this system has been associated with more positive emotions in a wide variety of contexts. It will be examined as a direct predictor of future depressive symptoms, and also as a moderator of personal vulnerabilities and stressors. This research will enhance our scientific understanding of the complex interplay of emotional and autonomic risk factors for depression following cancer diagnosis. It also holds future translational potential for identifying the highest-risk cases that might receive the greatest benefit from preventive interventions during the period of vulnerability following breast cancer diagnosis. Interventions aimed at enhancing psychological functioning in breast cancer patients through enhancing vagal control specifically may arise from this research.
-June 6, 2013