Pioneering Pancreatic Cancer Research at UCLA: Dr. Timothy Donahue and the Fight Against Adenosine
Pancreatic ductal adenocarcinoma remains one of the most formidable and deadly cancers. Researchers at the UCLA Health Jonsson Comprehensive Cancer Center are at the forefront of the battle against this disease, armed with a $4 million grant from the National Cancer Institute. This funding fuels their work to advance immune-based therapies, offering hope for improved treatments and outcomes for those diagnosed with this aggressive cancer.
The UCLA Team: A Multidisciplinary Approach
The research is spearheaded by a team of distinguished experts: Dr. Timothy Donahue, chief of surgical oncology and professor of surgery at the David Geffen School of Medicine at UCLA; Dr. Zev Wainberg, co-director of the UCLA Health GI Oncology Program; and Dr. Caius Radu, professor of molecular and medical pharmacology. This collaborative team integrates expertise in cancer cell biology, tumor immunology, clinical trials, bioinformatics, biostatistics, and mass spectrometry. This comprehensive approach is crucial for unraveling the complexities of pancreatic cancer and developing effective therapies.
Adenosine: Understanding the Enemy Within
At the heart of this research lies a focus on adenosine, a molecule naturally present in the body. In the context of pancreatic cancer, adenosine plays a detrimental role by suppressing the immune system. The UCLA team is dedicated to understanding precisely how adenosine manipulates the tumor environment and interferes with the crucial interactions between cancer cells and immune cells. By elucidating these mechanisms, researchers aim to identify novel therapeutic targets that can disrupt adenosine's suppressive effects.
Targeting Adenosine for Improved Outcomes
The ultimate goal is to develop new therapies that specifically target adenosine, thereby boosting the immune system's ability to fight pancreatic cancer. This innovative approach holds the promise of significantly improving treatment outcomes and enhancing the overall health of patients while reducing the burden of this devastating disease. The recent 1A/1B trial, which evaluated just the PD-1 and chemotherapy combination, showed promising results, but the team found an increased adenosine signaling in post-treatment tumors that posed a significant challenge to sustained anti-tumor immunity.
Clinical Trial: A Step Towards New Treatment Strategies
The grant will also support a follow-up phase 1/2 clinical trial. This trial will investigate the effects of combining a small molecule inhibitor with the existing treatment regimen of PD-1, an immunotherapy drug, and chemotherapy administered before surgery. “By introducing a small molecule inhibitor of to the existing chemotherapy and PD-1 inhibition regimen, we hope to limit adenosine production in the tumor microenvironment, thereby enhancing the immune response against the cancer,” said Donahue. The rationale behind this combination therapy is to limit adenosine production within the tumor microenvironment, thereby unleashing the immune system to effectively target and destroy cancer cells.
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Dr. Timothy Donahue: A Leader in Pancreatic Cancer Research
Dr. Timothy R. Donahue embodies a commitment to advancing the field through both surgical expertise and dedicated research. In addition to being a pancreatic surgeon, he runs a NIH funded laboratory that is focused on pancreatic cancer tumor biology and metabolism. The overall goal of his research is to identify new therapeutic combinations for patients with pancreatic cancer through a fundamental mechanistic investigation. As Chief of the Division of Surgical Oncology and Professor of Surgery at the David Geffen School of Medicine at UCLA, he also holds a joint appointment in the Department of Molecular and Medical Pharmacology, further bridging the gap between clinical practice and research innovation. He holds the Gary Shandling Chair in Pancreatic Surgery.
Dr. Donahue's dedication extends to his role as the Surgical Director of the UCLA Agi Hirshberg Center for Pancreatic Diseases. He is a very busy pancreatic surgeon and performs three to four pancreatic surgeries per week. He and his team perform the most complex of operations and have amongst the best outcomes in the world. He is genuinely interested in caring for patients with pancreatic cancer and making sure they receive state-of-the-art care.
Research Focus: Unraveling the Tumor Microenvironment
Dr. Donahue's research laboratory delves into the intricate details of pancreatic cancer tumor biology and metabolism. Specifically, his laboratory studies the impact of the tumor microenvironment, and the cross-talk between metabolism and signaling to identify co-dependencies of pancreas cancer tumor cells. His work aims to discover novel therapeutics and personalized treatment strategies for pancreatic cancer patients. By understanding how the tumor microenvironment influences cancer cell behavior, Dr. Donahue's team seeks to identify vulnerabilities that can be exploited for therapeutic benefit.
Key Publications: Contributions to the Field
Dr. Donahue's extensive research has resulted in numerous publications in high-impact journals. These publications cover a range of topics, including:
Integrative Survival-Based Molecular Profiling of Human Pancreatic Cancer: This study, published in Clinical Cancer Research, utilized molecular profiling to identify subtypes of pancreatic cancer with different survival outcomes, providing valuable insights for personalized treatment strategies. (Donahue, T.R., Tran, L.M., Hill, R., Li, Y., Kovochich A., Calvopina, J.H., Patel, S.G., Wu, N., Hindoyan, A., Farrell, J.J., Li, X., Dawson, D.W., Wu, H., "Integrative Survival-Based Molecular Profiling of Human Pancreatic Cancer." Clinical Cancer Research, 18(5): 1352-63, 2012.)
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Low expression of the E3 ubiquitin ligase CBL confers chemoresistance in human pancreatic cancer and is targeted by epidermal growth factor receptor inhibition: Published in Clinical Cancer Research, this research explored the mechanisms of chemoresistance in pancreatic cancer and identified a potential therapeutic target to overcome this resistance. (Kadera BE, Toste PA, Wu N, Li L, Nguyen AH, Dawson DW, Donahue TR, "Low expression of the E3 ubiquitin ligase CBL confers chemoresistance in human pancreatic cancer and is targeted by epidermal growth factor receptor inhibition," Clin Cancer Res, 2014, Oct 27.)
Downstaging Chemotherapy (DCTx) May Alter The Classic CT/MRI Signs of Vascular Involvement in Patients with Pancreaticobiliary Cancers. This Should Influence Patient Selection for Surgery: This article, featured in Archives of Surgery, investigated the impact of downstaging chemotherapy on the assessment of vascular involvement in pancreaticobiliary cancers, highlighting the importance of accurate imaging for surgical planning. (Donahue, T.R., Isacoff, W.H., Hines, O.J., Tomlinson J.S., Farrell, J.J., Bhat, Y.M., Garon, E., Clerkin, B.M., Reber, H.A., "Downstaging Chemotherapy (DCTx) May Alter The Classic CT/MRI Signs of Vascular Involvement in Patients with Pancreaticobiliary Cancers. This Should Influence Patient Selection for Surgery." Archives of Surgery, 146(7): 836-43, 2011.)
Locally advanced pancreatic cancer: association between prolonged preoperative treatment and lymph-node negativity and overall survival: This study, published in JAMA Surgery, examined the relationship between prolonged preoperative treatment, lymph node status, and survival in patients with locally advanced pancreatic cancer. (Kadera BE, Sunjaya DB, Isacoff WH, Li L, Hines OJ, Tomlinson JS, Dawson DW, Rochefort MM, Donald GW, Clerkin BM, Reber HA, Donahue TR, "Locally advanced pancreatic cancer: association between prolonged preoperative treatment and lymph-node negativity and overall survival." JAMA Surgery, 149(2): 145-53, 2014.)
CA19-9 Normalization During Pre-operative Treatment Predicts Longer Survival for Patients with Locally Progressed Pancreatic Cancer: This research, published in J Gastrointest Surg, demonstrated that normalization of the CA19-9 tumor marker during preoperative treatment is a predictor of longer survival in patients with locally advanced pancreatic cancer. (Williams JL, Kadera BE, Nguyen AH, Muthusamy VR, Wainberg ZA, Hines, OJ, Reber HA, Donahue TR, "CA19-9 Normalization During Pre-operative Treatment Predicts Longer Survival for Patients with Locally Progressed Pancreatic Cancer," J Gastrointest Surg. 20(7):1331-42, 2016.)
Chemotherapy-induced Inflammatory Gene Signature and Pro-tumorigenic Phenotype in Pancreatic CAFs via Stress-associated MAPK: This article, featured in Mol Cancer Res, investigated the effects of chemotherapy on pancreatic cancer-associated fibroblasts (CAFs) and identified a chemotherapy-induced inflammatory gene signature that promotes tumor growth. (Toste PA, Nguyen AH, Kadera BE, Duong M, Wu N, Gawlas I, Tran LM, Bikhchandani M, Li L, Patel SG, Dawson DW, Donahue TR, "Chemotherapy-induced Inflammatory Gene Signature and Pro-tumorigenic Phenotype in Pancreatic CAFs via Stress-associated MAPK," Mol Cancer Res, 14(5): 437-47, 2016.)
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Pancreatic cancer patients with lymph node involvement by direct tumor extension have similar survival to those with node-negative disease: This research, published in J Surg Onc, compared the survival outcomes of pancreatic cancer patients with lymph node involvement due to direct tumor extension to those with node-negative disease. (Williams JL, Nguyen AH, Rochefort M, Muthusamy VE, Wainberg ZA, Dawson DW, Tomlinson JS, Hines OJ, Reber HA, Donahue TR, "Pancreatic cancer patients with lymph node involvement by direct tumor extension have similar survival to those with node-negative disease," J Surg Onc, 112(4):396-402, 2015.)
Current Indications for Surgery of Intraductal Papillary Mucinous Neoplasms May Overlook Some Patients with Cancer: Recommendations for Change: This article, featured in J. Gastrointest Surg., suggested that current surgical guidelines for intraductal papillary mucinous neoplasms (IPMNs) may overlook some patients with cancer and proposed recommendations for change. (Nguyen AH, Toste P, Farrell JJ, Clerkin BM, Muthusamy VR, Watson R, Tomlinson JS, Hines OJ, Reber HA, Donahue TR, "Current Indications for Surgery of Intraductal Papillary Mucinous Neoplasms May Overlook Some Patients with Cancer: Recommendations for Change," J. Gastrointest Surg., 19(2): 258 - 65, 2015.)
Nonfunctional pancreatic neuroendocrine tumors < 2 cm on preoperative imaging are associated with a low incidence of nodal metastases and an excellent overall survival: This study, published in J Gastrointest Surgery, examined the outcomes of patients with small, nonfunctional pancreatic neuroendocrine tumors and found a low incidence of nodal metastases and excellent overall survival. (Toste PA, Kadera BE, Tatishchev SF, Dawson DW, Clerkin BM, Muthusamy R, Watson R, Tomlinson JS, Hines OJ, Reber HA, Donahue TR, "Nonfunctional pancreatic neuroendocrine tumors < 2 cm on preoperative imaging are associated with a low incidence of nodal metastases and an excellent overall survival." J Gastrointest Surgery, 17(12):2105-13, 2013.)
Endoscopically acquired pancreatic cyst fluid microRNA 21 and 221 are associated with invasive cancer: This research, published in the American Journal of Gastroenterology, demonstrated that the presence of microRNAs 21 and 221 in pancreatic cyst fluid is associated with invasive cancer. (Farrell JJ, Toste PM, Wu N, Li L, Li X, Lin TM, Wong J, Wu X, Dawson DW, Wu H, Donahue TR, "Endoscopically acquired pancreatic cyst fluid microRNA 21 and 221 are associated with invasive cancer," American Journal of Gastroenterology, 2013 Aug;108(8):1352-9.)
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