KRAS Mutant Pancreatic Cancer: No Lone Path to an Effective Treatment

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers with a dismal 7% 5-year survival rate and is projected to become the second leading cause of cancer-related deaths by 2020. KRAS is mutated in 95% of PDACs and is a well-validated driver of PDAC growth and maintenance. However, despite comprehensive efforts, an effective anti-RAS drug has yet to reach the clinic. Different paths to inhibiting RAS signaling are currently under investigation in the hope of finding a successful treatment. Recently, direct RAS binding molecules have been discovered, challenging the perception that RAS is an “undruggable” protein. Other strategies currently being pursued take an indirect approach, targeting proteins that facilitate RAS membrane association or downstream effector signaling. Unbiased genetic screens have identified synthetic lethal interactors of mutant RAS. Most recently, metabolic targets in pathways related to glycolytic signaling, glutamine utilization, autophagy, and macropinocytosis are also being explored. Harnessing the patient’s immune system to fight their cancer is an additional exciting route that is being considered. The “best” path to inhibiting KRAS has yet to be determined, with each having promise as well as potential pitfalls. We will summarize the state-of-the-art for each direction, focusing on efforts directed toward the development of therapeutics for pancreatic cancer patients with mutated KRAS

A comprehensive overview of radioguided surgery using gamma detection probe technology

The concept of radioguided surgery, which was first developed some 60 years ago, involves the use of a radiation detection probe system for the intraoperative detection of radionuclides. The use of gamma detection probe technology in radioguided surgery has tremendously expanded and has evolved into what is now considered an established discipline within the practice of surgery, revolutionizing the surgical management of many malignancies, including breast cancer, melanoma, and colorectal cancer, as well as the surgical management of parathyroid disease. The impact of radioguided surgery on the surgical management of cancer patients includes providing vital and real-time information to the surgeon regarding the location and extent of disease, as well as regarding the assessment of surgical resection margins. Additionally, it has allowed the surgeon to minimize the surgical invasiveness of many diagnostic and therapeutic procedures, while still maintaining maximum benefit to the cancer patient. In the current review, we have attempted to comprehensively evaluate the history, technical aspects, and clinical applications of radioguided surgery using gamma detection probe technology

Determining the mechanism underlying the effect of chloroquine in combination with an ERK inhibitor on pancreatic cancer cell proliferation

Background: Pancreatic cancer has a dismal 5-year survival rate of 9%. KRAS is mutated in 98% of pancreatic ductal adenocarcinomas (PDACs), making the discovery of a treatment for KRAS mutant cancers urgent. However, over 30 years of effort have yet to yield a direct anti-KRAS therapeutic, thus a current focus of the field is targeting downstream effectors of mutant KRAS. Hypothesis: We hypothesize that the synergy seen between SCH772984 (SCH), an ERK inhibitor, and chloroquine, an inhibitor of lysosomal acidification, is due to the ability of chloroquine to block the cell from harnessing energy through autophagy. Methods: HPAC, PANC-1, Pa14C and Pa01C cell lines were treated with a combination of SCH and autophagy specific inhibitors Spautin-1, SBI-0206965 (SBI), and MRT68921 (MRT). Cells were treated with the drugs alone and in combination with SCH for 72 hours, and proliferation assays were used to quantify the effect on cell growth. In a parallel line of investigation, ATG5 and ATG7 were genetically silenced using shRNA in a panel of PDAC cell lines. Following western blot analyses to confirm ATG5 or ATG7 knockdown, the sensitivity of these cells to SCH were compared to that of parental cells using proliferation after 72 hours of treatment as a readout. Results: Each autophagy inhibitor analyzed synergized with SCH in multiple PDAC cell lines. For these studies, the autophagy inhibitors were held at constant concentrations, while the SCH concentration was varied. Each of the drugs displayed the most synergy with SCH at concentrations ranging from 0.156μM to 1.25μM. MRT consistently showed the most synergy in our studies. In addition, growth curves of PDAC cells with ATG5 or ATG7 knockdown demonstrated that genetic silencing of autophagy-related proteins increase sensitivity to SCH treatment compared to wild type. PDAC cells became more sensitive to SCH following each of these forms of autophagy inhibition in our studies. Conclusion: Each of the autophagy inhibitors synergized with the ERK inhibitor in multiple PDAC cell lines. Additionally, cells in which vital autophagy genes, ATG5 or ATG7, were knocked down were more sensitive to SCH. These findings suggest that the synergy between chloroquine and SCH is at least partially due to the inhibition of autophagy.Bachelor of Science in Public Healt

KRAS Mutant Pancreatic Cancer: No Lone Path to an Effective Treatment

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers with a dismal 7% 5-year survival rate and is projected to become the second leading cause of cancer-related deaths by 2020. KRAS is mutated in 95% of PDACs and is a well-validated driver of PDAC growth and maintenance. However, despite comprehensive efforts, an effective anti-RAS drug has yet to reach the clinic. Different paths to inhibiting RAS signaling are currently under investigation in the hope of finding a successful treatment. Recently, direct RAS binding molecules have been discovered, challenging the perception that RAS is an “undruggable” protein. Other strategies currently being pursued take an indirect approach, targeting proteins that facilitate RAS membrane association or downstream effector signaling. Unbiased genetic screens have identified synthetic lethal interactors of mutant RAS. Most recently, metabolic targets in pathways related to glycolytic signaling, glutamine utilization, autophagy, and macropinocytosis are also being explored. Harnessing the patient’s immune system to fight their cancer is an additional exciting route that is being considered. The “best” path to inhibiting KRAS has yet to be determined, with each having promise as well as potential pitfalls. We will summarize the state-of-the-art for each direction, focusing on efforts directed toward the development of therapeutics for pancreatic cancer patients with mutated KRAS