Category: Research Publications

AACR 2014: IL10 autoregulatory loop displays promise as new therapeutic target for DLBCL

shaknovich_rBy Rita Shaknovich MD, PHD

Diffuse large B cell lymphoma (DLBCL) is a common aggressive lymphoma that represents 30-40% of newly diagnosed cases of non-Hodgkin lymphoma, but accounts for up to 80% of lymphoma-related deaths. Although R-CHOP remains the standard first line therapy, it has more recently been associated with a frequent lack of response in DLBCL patients. This lack of response has enforced the necessity for finding alternate therapeutic targets.

At the 2014 meeting of the American Association for Cancer Research researchers from Weill Cornell Medical College reported on their recent findings. In a late breaking abstract the Shaknovich Lab reported on the potential of the IL10 receptor as a new biomarker and therapeutic target in DLBCL. The  hypothesis is that DLBCL is dependent on the feed-forward autostimulatory loop that begins from the autocrine IL10 secretion and stimulation of overexpressed receptors leading to cell proliferation and that blocking the receptor would lead to cell death.

The research team of postdoctoral fellow Wendy Beguelin and research associate Seema Sawh determined that blocking IL10R results in specific inhibition of signaling through JAK1/2 and loss of phosphorylation at STAT3Y705 immediately after treatment. The inhibition of signaling through MAPK and phosphorylation of STAT3S727 came at a later time in treatment. The inhibition of signaling was sustained for days with only one drug treatment leading to induction of apoptosis. Anti-IL10R treatment resulted in significant downregulation of IL10 and IL10RA transcription, leading to interruption of IL10-IL10R autostimulatory loop.

IL10R is a novel therapeutic target in DLBCL that allows for easy detection and targeting. Shaknovich Lab is planning further animal studies and hopes to develop therapeutic antibody for clinical use in patients.

Palbociclib Displays Promising Results

Palbociclib (PD 0332991) is generating significant excitement according to an April 6th online article from the New York Times. The article cites the results of a recently reported phase II trial in which women with metastatic breast cancer were randomized to receive letrozole plus palbociclib or letrozole alone. Women receiving the combination had their risk of progression cut in half compared to the group that received letrozole alone. These results come roughly one year after the FDA granted Breakthrough Therapy designation to palbociclib, which may help speed up the drug approval process.

Palbociclib is a highly specific oral drug that binds to and inhibits a specific subtype of enzymes called cyclin-dependent kinases (CDK). The same enzymes are critical to the development and progression of mantle cell lymphoma (MCL). Investigators at Weill Cornell Medical College have been leading the evaluation of palbociclib in MCL. Within the next month, we will open a phase I trial evaluating the combination of palbociclib plus ibrutinib in patients with previously treated MCL. For additional information regarding the upcoming trial or other trials in lymphoma, call Amelyn Rodriguez, RN at (212) 746-1362 or e-mail Amelyn at amr2017@med.cornell.edu.

Tumor Blood Vessel Signals Linked to Cancer Lethality

Although the importance of blood vessels to cancer growth is well established, researchers at Weill Cornell Medical College recently found, that the cells that line the blood vessels of tumors are important in promoting the change of a slow-growing malignancy into aggressive, disease resistant strains.

Their finding, in the March 17 issue of Cancer Cell , challenges what was believed to be a fundamental dogma in cancer. It suggests that it is not simply the number of genetic mutations that occur in cancer cells that determines the aggressiveness of the disease. Rather, lethality occurs when the cancer hijacks the reparative function of blood vessels, a critical step that ensures tumor cells’ ability to spread and resist treatment.

The researchers also found the crucial nurturing molecules that cancer co-opts from tumor blood vessels to promote invasiveness and resistance to chemotherapy. They show in animal experiments that shutting down these previously unrecognized biological signals originating from tumor vessels makes cancer less aggressive and improves survival.

“The endothelial cells that line the vessels orchestrate a wide variety of biological processes — good and bad,” says the study’s senior investigator, Dr. Shahin Rafii, co-director of Weill Cornell’s Ansary Stem Cell Institute and Tri-Institutional Stem Cell Initiative, and a professor of Genetic Medicine. Dr. Rafii also is the founder of Angiocrine Bioscience, a startup anchored at Weill Cornell that is investigating how endothelial cells might be used to heal damaged tissues and regenerate organs – as well as target tumors. “The understanding and control of blood vessel function and how this changes the malignant behaviors of cancer cells is a transformative concept and will pave the way for designing innovative treatments that disrupt signals from the local environment housing the tumor cells- a strategy that has been unappreciated.”