AACR 2019 Research Roundup: Pancreatic Cancer Immunotherapy, Prostate Cancer Drug Resistance, Insight into Inherited Cancer Mutations

AACR 2019 Annual Meeting

The AACR annual meeting, held this year in Atlanta, highlights the work of leading cancer researchers from institutions all over the world.

Combination Treatment for Advanced Pancreatic Cancer

Pancreatic cancer is one of the most difficult types of cancer to treat. So far, immunotherapy has not been effective in people with these tumors. A study led by members of the Parker Institute for Cancer Immunotherapy and the Cancer Research Institute demonstrated that adding two different types of immunotherapy to chemotherapy shows promise for treating advanced pancreatic cancer.

The phase Ib clinical trial combined standard chemotherapy with the checkpoint inhibitor drug nivolumab (Opdivo®) and an experimental antibody called APX005M. This antibody enhances the immune response by binding to a receptor called CD40. An analysis showed that 20 of 24 patients who got this combination had their tumors shrink. The researchers believe the three treatments work in a synergistic way.

All of the people in the study had metastatic pancreatic cancer that had not previously been treated. About half of the patients eventually experienced side effects, however, some of which required stopping therapy. Some individuals were on the treatment for about a year and continued to show a response. But it is too early to know the effect the drug combination has on how long people survive.

“Pancreatic cancer has a challenging prognosis, so to see patients continuing on this treatment for this long is promising,” says MSK medical oncologist Eileen M. O’Reilly, who was co-lead author of the study. Based on the initial results, the trial has proceeded to a randomized phase II trial, which will complete enrollment in the near future.

This study was funded by the Parker Institute for Cancer Immunotherapy and the Cancer Research Institute. Clinical trials at MSK also receive funding from the National Cancer Institute. MSK has received research funding from Celgene, AstraZeneca, ActaBiologica, and Genentech-Roche. Dr. O’Reilly has advised and consulted to Celgene, Bayer, Bristol-Myers Squibb, and BioLineRx.

Prostate Cancer Drug Resistance: A New Player

Advanced prostate cancer can be effectively treated with hormone therapy, which blocks the cancer-fueling effects of testosterone. But the disease almost always becomes resistant to these drugs over time. Researchers have suspected that this resistance may be promoted in part by the tumor microenvironment. This includes the noncancerous cells, molecules, and blood vessels that surround a cluster of cancer cells.

Recent studies have pointed to the importance of one specific cell type, called cancer-associated fibroblasts (CAF). CAFs in the microenvironment are clearly involved in helping prostate tumors grow and resist some treatments. But it has not been clear whether they contribute specifically to resistance to hormone therapy.

Zeda Zhang, a graduate student in the laboratory of physician-scientist Charles Sawyers at MSK, presented research showing that CAFs do promote resistance to hormone therapy. The cells secrete a protein called NRG1, which binds to a receptor called HER3 on the surface of prostate cancer cells. This sends a signal into the cancer cells to reactivate growth.

The researchers used human prostate cancer tissue implanted into mice. The results showed blocking the NRG1-HER3 signal made hormone-resistant tumors sensitive to the therapy once again. The finding suggests that targeting NRG1 could restore this sensitivity in men with advanced prostate cancer whose tumors have become resistant to the drugs.

“One important thing we still need to learn is whether NRG1 promotes resistance from the very beginning of the disease or if it starts in response to the hormone therapy,” Mr. Zhang explains. “That would affect which patients might receive drugs blocking the protein. We hope to get a clearer idea with further research.”

Do Inherited Cancer Mutations Always Have a Cancer-Causing Effect?

Scientists know that cancer is the result of changes in DNA that distort cell behavior. What is less clear is how inherited changes interact with other DNA alterations that occur during a tumor’s development.

Scientists in the labs of Barry Taylor and Michael Berger at MSK are mining the mountains of data emerging from MSK’s DNA sequencing test, called MSK-IMPACT™. Their goal is to tease out the relative importance of these genetic factors. At the AACR meeting, three members of these labs are presenting posters on what they are learning from studying this massive dataset, which currently contains genomic information from more than 30,000 people with advanced cancer.

BRCA Mutations: Germline and Somatic

Computational biologist Philip Jonsson has been using this large dataset to study tumors with mutations in the genes BRCA1 and BRCA2. These genes encode proteins that repair damaged DNA. With hobbled or missing BRCA proteins, cells accumulate more DNA damage that can lead to cancer. 

BRCA mutations are known to lead to an increased risk of several types of cancer, including breast, ovarian, prostate, and pancreatic. The role that these mutations may play in other types of cancer is less well understood. Also a mystery is how germline (inherited) and somatic (acquired) mutations in these genes may interact to promote cancer. 

On April 1, Dr. Jonsson is presenting data showing that both germline and somatic BRCA mutations are indeed more common in breast, ovarian, prostate, and pancreatic tumors compared with other types of cancer. What’s more, these same tumor types are also the ones in which both copies of a BRCA gene are commonly mutated. A mutation in the second copy is a sign that the cancer is dependent on that genetic alteration.

In other common cancers — lung and colorectal, for example — Dr. Jonsson found the prevalence of such double hits to be more rare. To him, this implied that germline mutations in BRCA genes were just along for the ride rather than playing a role in tumor development. The upshot, Dr. Jonsson says, is that “not all BRCA mutations are equal.”

This distinction matters because tumors with BRCA mutations are thought of as good candidates for drugs called PARP inhibitors. But what these new data suggest is that having a BRCA mutation doesn’t necessarily mean a tumor is dependent on it. And if that’s the case, then the PARP inhibitor won’t provide any benefit.

Lynch Syndrome and Microsatellite Instability

The lessons learned from this MSK-IMPACT dataset do not stop there. Preethi Srinivasan, a graduate student in the Berger lab, and Chaitanya Bandlamudi, a computational biologist in the Center for Molecular Oncology at MSK, used this same dataset to explore the interplay between germline and somatic mutations in people with Lynch syndrome. Lynch is a genetic disease that is associated with a high risk of cancer, particular colorectal cancer. Ms. Srinivasan is presenting this work on April 2.

People with Lynch syndrome have germline mutations in specific DNA repair genes that fix a type of damage called a DNA mismatch. Their tumors often demonstrate a higher-than-normal degree of DNA changes, a state referred to as microsatellite instability. Ms. Srinivasan and Dr. Bandlamudi wanted to know whether mutations in both copies of a DNA repair gene are required to cause microsatellite instability.

What our results suggest is that if you have Lynch syndrome, but your tumor is not microsatellite unstable, you might not be a good candidate for immunotherapy.
Preethi Srinivasan Graduate Student

Among 112 patients with Lynch syndrome being treated for cancer at MSK, 71% had mutations in both versions — both alleles — of a DNA mismatch repair gene. Most of these people had tumors with microsatellite instability. Only one out of 31 tumors with one mutated and one normal allele had microsatellite instability. The finding indicates that loss of function in both DNA mismatch repair alleles is typically required to cause microsatellite instability.

However, as with BRCA genes, where the tumor came from made a difference. The researchers did not detect microsatellite instability in Lynch syndrome patients with breast, lung, and thyroid cancers even when these tumors had mutations in both DNA mismatch repair alleles.

“There’s a lot of interest in Lynch syndrome and microsatellite unstable tumors because they tend to respond very well to immunotherapy,” Ms. Srinivasan says. “What our results suggest is that if you have Lynch syndrome, but your tumor is not microsatellite unstable, you might not be a good candidate for immunotherapy.”

Drivers versus Passengers

Finally, Dr. Bandlamudi and Ms. Srinivasan leveraged this same dataset to look at the entire suite of germline mutations tested by MSK-IMPACT. Their findings, which Dr. Bandlamudi presented on March 31, echo those of the other two studies. Namely, it was only when both copies of a gene were mutated that a person experienced an earlier onset of cancer or that their tumors demonstrated clear effects of the mutation. But these double hits were common in only certain types of cancer. In fact, they found that 27% of all tumors in people with a known high-risk germline allele are likely sporadic cancers whose development was unrelated to the germline mutation.

“These results suggest a new conceptual paradigm is needed for understanding the role of inherited mutations in cancer development,” Dr. Bandlamudi says. “The long-standing all-or-none approach that determines whether a key damaging inherited mutation is present or absent is not sufficient to understand its role in the development of cancer in individual people. Context is king.”

These studies from the Taylor and Berger laboratories were made possible by collaborations between the Marie-Josée and Henry R. Kravis Center for Molecular Oncology, the Niehaus Center for Inherited Cancer Genomics, and the Molecular Diagnostics Service in the Department of Pathology at MSK.