Pancreatic cancer: progress, challenges, and hope

Over the past two decades, remarkable progress has been made in understanding the biological underpinnings of many cancers. Survival of patients with the top four leading causes of cancer deaths in the U.S., carcinomas of the lung, colon and rectum, breast, and prostate, has dramatically increased. In sharp contrast, survival in patients with pancreatic ductal adenocarcinoma (PDAC) has not changed significantly. PDAC is currently the fourth leading cause of cancer death in the U.S., but it is expected to account for more deaths than colorectal, breast, or prostate cancer by 2020, as the incidence of this cancer continues to rise and survival continues to be shockingly brief (median survival of 6 months). Nab-paclitaxel recently became the first FDA-approved drug for advanced PDAC in many years – based on an improvement of 2 months in median survival.

A better understanding of the underlying biology of PDAC is required to even consider the possibility of clinical trials yielding survival on the scale of years as opposed to months. For too long, lessons learned from the study of other cancers have been hastily applied to pancreas cancer, with lackluster results and deleterious costs to our patients. Scientists have only recently fully embraced that the biology of PDAC is unique. Under the microscope, PDAC looks different, owing to an aggressive desmoplastic response – an amalgamation of activated fibroblasts, macrophages and other inflammatory cells admixed with profuse scar tissue. Moreover, pancreas tumors are uniquely hypovascular.

Cancer cells that persist in this cauldron of hypoxia and acidity have likely evolved survival mechanisms that are particular to this disease and produce cells that are particularly resistant to therapy. One such survival mechanism is the ability to seed distant organs; this may occur surprisingly early in the course of PDAC. Furthermore, with limited blood flow within tumors, impaired delivery of systemic chemotherapy is a unique and pressing issue in PDAC.

Despite past failures, our field has recalibrated and rebooted, and we are now poised to make serious inroads against this disease. Scientists and clinicians have recently developed novel tools that will enable new discoveries that will translate to the clinic. Novel, genetically engineered mouse models have catalyzed our understanding of PDAC while also serving as a more faithful model for testing novel drugs. Vogelstein and colleagues at Johns Hopkins utilized advanced sequencing technologies to define the genomic landscape of PDAC, enabling many to identify novel drug targets and develop new assays for early diagnosis utilizing state-of-the-art microfluidic technology. Others have begun to tackle the drug delivery problem in PDAC with nanoparticle vehicles and other targeted modalities. Finally, the manipulation and engineering of the patient\'s immune system to target nascent PDAC cells is an area of intense investigation and represents perhaps one of the most promising therapeutic strategies in our armamentarium.

After many years in the dark, we are poised to enter a new age – an Age of Enlightenment for pancreatic cancer. There is no more promising time for pancreatic cancer research than the present, as we now have a plethora of new tools to understand this disease. And with better understanding, we will undoubtedly be in a better position to deliver to our patients what they sorely need most: hope for survival on the scale of years, as opposed to months.

Dr. Rhim is assistant professor of internal medicine and assistant director for translational research, division of gastroenterology, department of internal medicine, University of Michigan, Ann Arbor. His comments were made during the ASGE and AGA joint Presidential Plenary at the annual Digestive Disease Week.

Over the past two decades, remarkable progress has been made in understanding the biological underpinnings of many cancers. Survival of patients with the top four leading causes of cancer deaths in the U.S., carcinomas of the lung, colon and rectum, breast, and prostate, has dramatically increased. In sharp contrast, survival in patients with pancreatic ductal adenocarcinoma (PDAC) has not changed significantly. PDAC is currently the fourth leading cause of cancer death in the U.S., but it is expected to account for more deaths than colorectal, breast, or prostate cancer by 2020, as the incidence of this cancer continues to rise and survival continues to be shockingly brief (median survival of 6 months). Nab-paclitaxel recently became the first FDA-approved drug for advanced PDAC in many years – based on an improvement of 2 months in median survival.

A better understanding of the underlying biology of PDAC is required to even consider the possibility of clinical trials yielding survival on the scale of years as opposed to months. For too long, lessons learned from the study of other cancers have been hastily applied to pancreas cancer, with lackluster results and deleterious costs to our patients. Scientists have only recently fully embraced that the biology of PDAC is unique. Under the microscope, PDAC looks different, owing to an aggressive desmoplastic response – an amalgamation of activated fibroblasts, macrophages and other inflammatory cells admixed with profuse scar tissue. Moreover, pancreas tumors are uniquely hypovascular.

Cancer cells that persist in this cauldron of hypoxia and acidity have likely evolved survival mechanisms that are particular to this disease and produce cells that are particularly resistant to therapy. One such survival mechanism is the ability to seed distant organs; this may occur surprisingly early in the course of PDAC. Furthermore, with limited blood flow within tumors, impaired delivery of systemic chemotherapy is a unique and pressing issue in PDAC.

Despite past failures, our field has recalibrated and rebooted, and we are now poised to make serious inroads against this disease. Scientists and clinicians have recently developed novel tools that will enable new discoveries that will translate to the clinic. Novel, genetically engineered mouse models have catalyzed our understanding of PDAC while also serving as a more faithful model for testing novel drugs. Vogelstein and colleagues at Johns Hopkins utilized advanced sequencing technologies to define the genomic landscape of PDAC, enabling many to identify novel drug targets and develop new assays for early diagnosis utilizing state-of-the-art microfluidic technology. Others have begun to tackle the drug delivery problem in PDAC with nanoparticle vehicles and other targeted modalities. Finally, the manipulation and engineering of the patient\'s immune system to target nascent PDAC cells is an area of intense investigation and represents perhaps one of the most promising therapeutic strategies in our armamentarium.

After many years in the dark, we are poised to enter a new age – an Age of Enlightenment for pancreatic cancer. There is no more promising time for pancreatic cancer research than the present, as we now have a plethora of new tools to understand this disease. And with better understanding, we will undoubtedly be in a better position to deliver to our patients what they sorely need most: hope for survival on the scale of years, as opposed to months.

Dr. Rhim is assistant professor of internal medicine and assistant director for translational research, division of gastroenterology, department of internal medicine, University of Michigan, Ann Arbor. His comments were made during the ASGE and AGA joint Presidential Plenary at the annual Digestive Disease Week.

Over the past two decades, remarkable progress has been made in understanding the biological underpinnings of many cancers. Survival of patients with the top four leading causes of cancer deaths in the U.S., carcinomas of the lung, colon and rectum, breast, and prostate, has dramatically increased. In sharp contrast, survival in patients with pancreatic ductal adenocarcinoma (PDAC) has not changed significantly. PDAC is currently the fourth leading cause of cancer death in the U.S., but it is expected to account for more deaths than colorectal, breast, or prostate cancer by 2020, as the incidence of this cancer continues to rise and survival continues to be shockingly brief (median survival of 6 months). Nab-paclitaxel recently became the first FDA-approved drug for advanced PDAC in many years – based on an improvement of 2 months in median survival.

A better understanding of the underlying biology of PDAC is required to even consider the possibility of clinical trials yielding survival on the scale of years as opposed to months. For too long, lessons learned from the study of other cancers have been hastily applied to pancreas cancer, with lackluster results and deleterious costs to our patients. Scientists have only recently fully embraced that the biology of PDAC is unique. Under the microscope, PDAC looks different, owing to an aggressive desmoplastic response – an amalgamation of activated fibroblasts, macrophages and other inflammatory cells admixed with profuse scar tissue. Moreover, pancreas tumors are uniquely hypovascular.

Cancer cells that persist in this cauldron of hypoxia and acidity have likely evolved survival mechanisms that are particular to this disease and produce cells that are particularly resistant to therapy. One such survival mechanism is the ability to seed distant organs; this may occur surprisingly early in the course of PDAC. Furthermore, with limited blood flow within tumors, impaired delivery of systemic chemotherapy is a unique and pressing issue in PDAC.

Despite past failures, our field has recalibrated and rebooted, and we are now poised to make serious inroads against this disease. Scientists and clinicians have recently developed novel tools that will enable new discoveries that will translate to the clinic. Novel, genetically engineered mouse models have catalyzed our understanding of PDAC while also serving as a more faithful model for testing novel drugs. Vogelstein and colleagues at Johns Hopkins utilized advanced sequencing technologies to define the genomic landscape of PDAC, enabling many to identify novel drug targets and develop new assays for early diagnosis utilizing state-of-the-art microfluidic technology. Others have begun to tackle the drug delivery problem in PDAC with nanoparticle vehicles and other targeted modalities. Finally, the manipulation and engineering of the patient\'s immune system to target nascent PDAC cells is an area of intense investigation and represents perhaps one of the most promising therapeutic strategies in our armamentarium.

After many years in the dark, we are poised to enter a new age – an Age of Enlightenment for pancreatic cancer. There is no more promising time for pancreatic cancer research than the present, as we now have a plethora of new tools to understand this disease. And with better understanding, we will undoubtedly be in a better position to deliver to our patients what they sorely need most: hope for survival on the scale of years, as opposed to months.

Dr. Rhim is assistant professor of internal medicine and assistant director for translational research, division of gastroenterology, department of internal medicine, University of Michigan, Ann Arbor. His comments were made during the ASGE and AGA joint Presidential Plenary at the annual Digestive Disease Week.