Hackensack Meridian CDI Scientists Find One-Two Punch Working against Stubborn Pancreatic Cancer in Preclinical Models

By changing gene expression first, some immunotherapies may work better, models show

September 29, 2020 – Nutley, NJ – A one-two punch of changing gene expression, then deploying immune checkpoint inhibitors, shows promise in battling one of the most treatment-resistant types of cancer in preclinical models, according to a new publication including authors from the Hackensack Meridian Center for Discovery and Innovation (CDI).

Their research findings published Aug. 14 in the journal Cancer Research suggest that since some cancer treatments can be undermined by epigenetic changes (altered DNA methylation affecting gene expression) in cancer cells before the treatments are even administered, a worthwhile strategy is to administer an epigenetically-acting drug – which can pave the way for more effective subsequent use of immune-acting cancer treatments, the authors found.

“Overall, these findings in a model of aggressive pancreatic cancer have clear and promising implications for the design of future studies, both in mice and in human patients, to improve the effectiveness of epigenetic modulation, in combination with immune checkpoint inhibition,” said Benjamin Tycko, M.D., Ph.D., the CDI lab director who oversaw the study, along with his longtime colleague Tamas Gonda, M.D. “They also suggest a clear path forward for making further improvements.”

The tumor type – pancreatic ductal adenocarcinoma – is among the most deadly cancer types, since it has proven to be stubbornly resistant both to standard chemotherapy and more recent immunotherapies.

The researchers tested four protocols, which included the sequential use of decitabine, a DNA-hypomethylating drug, followed by immune checkpoint inhibitors. Among the effects documented in the data: the increase in crucial, and tumor-infiltrating, effector T cells, with this one-two punch.

Compared against the control group, there were no adverse side effects of adding decitabine, and the one-two punch of decitabine and the immune-acting agents doubled the average survival time in the model.

However, treatment was still not a cure, and the cancers ultimately progressed – perhaps partly because of a decitabine-induced increase in M2 macrophages, immune system cells which can inhibit therapeutic responses.

The researchers’ work continues, with further strategies including adding other epigenetic drugs, and also discovering ways to reduce the number of M2 macrophages – to potentially improve the response.

Authors of the study include colleagues from Columbia University, who have started working on an early-phase clinical trial in relation to the therapeutic combination. Additionally, motivated by the findings in pancreatic cancer, scientists at the CDI are now at work applying a similar approach in a multiple myeloma model. They are also starting new collaborations with investigators working on pancreatic cancer at the Georgetown Lombardi Comprehensive Cancer Center. John Theurer Cancer Center of Hackensack Meridian Health is a member of the Georgetown Lombardi Comprehensive Cancer Center Consortium.

A DNA hypomethylating drug alters the tumor microenvironment and improves the effectiveness of immune checkpoint inhibitors in a mouse model of pancreatic cancer.

Gonda TA, Fang J, Salas M, Do C, Hsu E, Zhukovskaya A, Siegel A, Takahashi R, Lopez-Bujanda ZA, Drake CG, Manji GA, Wang TC, Olive KP, Tycko B. Cancer Res. 2020 Aug 14:canres.0285.2020. doi: 10.1158/0008-5472.CAN-20-0285.

About the Center for Discovery and Innovation

The Center for Discovery and Innovation, a newly established member of Hackensack Meridian Health, seeks to translate current innovations in science to improve clinical outcomes for patients with cancer, infectious diseases and other life-threatening and disabling conditions. The CDI, housed in a fully renovated state-of-the-art facility, offers world-class researchers a support infrastructure and culture of discovery that promotes science innovation and rapid translation to the clinic.

About John Theurer Cancer Center at Hackensack University Medical Center

John Theurer Cancer Center at Hackensack University Medical Center is New Jersey's largest and most comprehensive center dedicated to the diagnosis, treatment, management, research, screenings, and preventive care as well as survivorship of patients with all types of cancers. The 14 specialized divisions covering the complete spectrum of cancer care have developed a close-knit team of medical, research, nursing, and support staff with specialized expertise that translates into more advanced, focused care for all patients. Each year, more people in the New Jersey/New York metropolitan area turn to John Theurer Cancer Center for cancer care than to any other facility in New Jersey. John Theurer Cancer Center is a member of the Georgetown Lombardi Comprehensive Cancer Center Consortium, one of just 16 NCI-approved cancer research consortia based at the nation's most prestigious institutions. Housed within a 775-bed not-for-profit teaching, tertiary care, and research hospital, John Theurer Cancer Center provides state-of-the-art technological advances, compassionate care, research innovations, medical expertise, and a full range of aftercare services that distinguish John Theurer Cancer Center from other facilities. For additional information, please visit www.jtcancercenter.org.