by Kerri Kaplan
An orphan disease
In the early 2000s, when Dr. Herman was a medical resident and the Lustgarten Foundation had recently been established, single-agent gemcitabine was the only first-line treatment available for metastatic pancreatic cancer. The goal of this chemotherapy was to improve quality of life and potentially offer a modest survival advantage. There also were few clinical trial options. Major academic centers might have one trial available, and often it was only for patients who were eligible for surgery. Little was known about pancreatic cancer because the research was practically non-existent, and scant attention was paid to the disease. Pancreatic cancer was truly considered an orphan disease. Dr. Herman noted, “The Lustgarten Foundation made a dramatic difference in increasing awareness and helping to bring urgency to this disease.” When asked what the most significant difference is 20 years later, he replies, “Hope.”
Twenty years ago, doctors didn’t understand enough about the disease to know which drugs would work best on each patient, and more importantly, which subsets of patients might respond differently to certain drugs. The Foundation’s early funding was focused on creating a better understanding of the mechanism driving the disease. Today, these discoveries are leading to more targeted approaches to treating pancreatic cancer.
A new focus on more effective treatments and personalized medicine
The Foundation launched the Robert F. Vizza Lustgarten Clinical Accelerator Initiative (CAI) to translate breakthroughs in the lab into new potential therapies in the clinic. As Dr. Rakeman explains, “The CAI plays a critical role in driving discoveries because these smaller, smarter trials are designed so that even if a trial fails, each patient’s tumor is meticulously analyzed, so what we learn from the clinic can be brought back to the lab.”
Additionally, the Foundation’s Therapeutics-Focused Research Program continues to identify new therapeutic approaches and drug targets to develop a robust pipeline for the CAI. This program focuses on four key areas to support the understanding of the causes and progression of pancreatic cancer: inflammation, metabolism, metastasis, and the stroma, which is the supportive tissue surrounding the pancreatic tumor that is difficult for treatments to penetrate.
Dr. Herman also explained that new technologies like organoids in pancreatic cancer pioneered in the Lustgarten dedicated laboratory at Cold Spring Harbor Lab have the potential to revolutionize how patients are treated. A fine-needle aspiration is used to obtain a sample from a patient’s tumor to make their organoid, a 3D cell culture of a patient’s tumor that replicates the characteristics of the cancer. Then the organoid can be “treated” with many compounds and combinations of compounds to determine which are most effective in killing the cancer cells. While research is still ongoing, scientists believe the drugs that work on the organoid will likely work on the patient, which is a huge step forward, as patients don’t have time to waste on treatments that will be ineffective for their specific tumor.
Currently, most doctors decide which first-line standard of care chemotherapy treatment to give patients based on their overall health and age, without knowing which treatment might be more effective in killing their tumor. In the recently launched Pancreatic Adenocarcinoma Signature Stratification trial, patients are randomly assigned to one of two standard of care chemotherapy regimens. At the same time, an organoid is made, and a thorough analysis of the tumor is performed to provide a deeper understanding of the patient’s response. The trial will confirm if the organoids effectively predict which of the two standard chemotherapy regimens should be given as first-line therapy, taking out the guesswork. Additionally, organoids could be used to personalize therapies for patients for second-line treatment.
Another recent improvement in care is that all pancreatic cancer patients undergo genetic testing for inherited genetic mutations, regardless of family history. About 10% of pancreatic cancer patients carry an inherited, germline mutation. In some cases, such as patients with BRCA mutations, treatments like PARP inhibitors and platinum-based chemotherapy drugs can be used, based on research demonstrating pancreatic tumors with the BRCA mutation often respond better to these treatments. For example, Keytruda® is FDA-approved for advanced pancreatic cancer patients with MSI high tumors. The Lustgarten Foundation played a critical role in bringing Keytruda® to patients by funding the research at Johns Hopkins, encouraging patients to get tested, and funding patients’ testing to determine if their tumors are MSI high.
The changing landscape for earlier detection
Knowing patients’ genetic mutations also enables patients to alert family members to undergo genetic testing if necessary. Family members identified as high-risk should receive surveillance for pancreatic cancer and consider enrolling in an early detection program offered at many hospitals. Dr. Herman noted that not only have therapeutics advanced in the past 20 years but so have early detection strategies for pancreatic cancer, which is of primary importance to those at high-risk. The CancerSEEK research lays the foundation for a single blood screening test for multiple cancers that could be offered as part of routine medical checks and represents a significant step forward in how pancreatic cancer may be diagnosed in the future. The Comprehensive Cyst (CompCyst) test combines clinical, radiological, genetic and protein marker information to classify pancreatic cysts to determine the best course of action—surgery or surveillance.
What’s on the horizon
Dr. Herman is energized by how far the field has come and the promising new therapies on the horizon. For example, the KRAS gene, mutated in most pancreatic cancer patients, was one of the first cancer genes ever identified. Yet despite that early discovery, progress in developing treatments attacking it has been slow. Scientists labeled the KRAS protein “undruggable” because its smooth, round shape made it difficult to develop drugs that could latch onto it and block its activities. In May 2021, the FDA’s approval of a new therapy designed to treat people with advanced lung cancer was one of the most exciting advances in cancer treatment. This targeted therapy stops the growth of tumors caused by a mutant version of the KRAS found in lung cancer and a very small subset of pancreatic cancer patients. This discovery has opened the door for new potential therapies for KRAS in pancreatic cancer, which would be an enormous breakthrough for this disease.
Dr. Herman closed by noting how the generosity of our donors makes discoveries in early detection and treatment possible. The Lustgarten Foundation is unique in that 100% of donations fund pancreatic cancer research, so we can transform pancreatic cancer into a curable disease. It is only with the continued support of our donors that we can achieve what Dr. Herman described as the most significant difference for patients in the past 20 years: HOPE.