Newswise — A number of Dana-Farber Cancer Institute faculty are presenting abstracts at the 2017 American Association for Cancer Research (AACR) Annual Meeting being held April 1-5, 2017 in Washington, DC.
The abstracts being presented by Dana-Farber faculty include: • Tumor models help predict response to immune checkpoint blockade• Using massively parallel sequencing to detect viral infection in tumor tissue• New patient-derived modeling system of post-treatment cancers to aid research into residual disease and second-line drug effectiveness • A powerful PRISM repurposes drugs to treat cancerTumor models help predict response to immune checkpoint blockade (Tumor Microenvironment 5)
Although checkpoint-blocking immunotherapy drugs can have dramatic benefits in some cancer patients, they often don’t work at all, and there is a need for better methods of predicting who will respond to the expensive drugs.
Scientists at Dana-Farber have developed a laboratory model system for measuring the response to drugs that block the PD-1 checkpoint, which is a target of the most potent immunotherapy agents in use currently – drugs like nivolumab and pembrolizumab.
Led by David Barbie, MD, and Kwok-Kin Wong, MD, PhD, the investigators sought to create miniature three-dimensional clusters, called spheroids, containing tumor cells as well as immune cells that surround and attempt to invade tumors to destroy them. Using both mouse and human tumor cells, they constructed tumor spheroids in the laboratory within a three-dimensional microfluidic system to which drugs and antibodies could be introduced. In addition, they studied mouse cancer models that did or did not respond to PD-1 checkpoint blockade, to determine what changes to look for in the tumor spheroids when they were exposed to the drugs. Using these results, the scientists analyzed the immune response to PD-1-inhibiting drugs in a large number of tumor spheroids made using samples from patients. They discovered in the laboratory cultured spheroids that induction of cytokines that recruit immune suppressive cells correlated with a lack of response in the patients to PD-1 blocking drugs. They further demonstrated the potential to this system to identify combination therapies with PD-1 blockade that could block these factors and reactivate the immune system in resistant tumors.
“Together, these data demonstrate the ability to profile the response to tumor PD-1 blockade ex vivo [in the laboratory] and unveil a novel strategy to advance precision immuno-oncology,” said Barbie and Wong.
The research (Control Number 17-A-5493-AACR) will be presented in a poster session Tuesday, April 4, from 8:00 to 12:00 noon.
Using massively parallel sequencing to detect viral infection in tumor tissueA technique that combines next-generation sequencing with special molecular probes can not only identify mutations and other genetic abnormalities in cancer tissue, but simultaneously indicate whether the tissue is infected by any of several types of viruses, Dana-Farber researchers will report in a poster session on April 2. The approach can help scientists explore the role that viruses play in many cancers, and potentially identify targets for future precision-medicine drugs, study leaders say. Viruses are known to cause up to 15 percent of human cancers, but probing tumor tissue for their presence has traditionally required completely different procedures than the massively parallel sequencing techniques used to identify aberrations such as genetic mutations and translocations. The new technique involves probes containing the DNA sequences of specific cancer-causing viruses. If any of these sequences matches a DNA segment in tumor tissue, it suggests the corresponding virus is present in the tumor cells, though additional steps will be needed to determine that the virus is causing disease. “If we could detect viral infection concurrently with genomic analysis, we could provide a more complete genetic profile than has been obtainable in the past from a single sample of tumor tissue,” said study lead author Laura MacConaill, PhD, of Dana-Farber.
The research (Control Number 17-A-4053-AACR) will be presented in a poster session Sunday, April 2, from 1:00 p.m. to 5:00 p.m.
New patient-derived modeling system of post-treatment cancers to aid research into residual disease and second-line drug effectiveness By adapting current methods of producing three-dimensional cultures of malignant tumors isolated from individual patients, investigators at Dana-Farber have devised a modeling system for tumors that have survived initial treatment with chemotherapy drugs. The technique, to be presented in a mini symposium on April 4, provides a way to generate cancer cells whose molecular profile and observable characteristics simulate those of tumor cells that survive in the patient after treatment. Such residual cancer cells, resistant to front-line chemotherapy agents, often form the core of recurrent and metastatic cancers. The new technique can help researchers simulate in the lab the drug-resistant tumors that emerge in individual patients and determine which second-line treatments may be effective in them. This could be accomplished by directly testing treatments on these residual cells or by identifying their targetable molecular abnormalities.
It represents a first-in-class model of cancer after treatment, said study leaders Constantine Mitsiades, MD, PhD, and Eugen Dhimolea, PhD, of Dana-Farber.“It gives researchers the ability to identify cancer vulnerabilities previously overlooked or unidentified by existing methods in a functional, personalized medicine setting,” Dhimolea remarked.
Although currently a research tool, the researchers intend to pursue future clinical tests to identify therapies that are likely to be effective in patients who become resistant to front-line agents. The research (Control Number 17-A-7155-AACR) will be presented at a mini symposium on Models for Treatment Resistance and Drug Discovery on Tuesday, April 4, from 3:00 p.m. to 5 p.m.
A powerful PRISM repurposes drugs to treat cancerTo complement the long and expensive investment to make new cancer drugs, scientists have devised a way to rapidly test thousands of existing drugs that might be repurposed to fight tumors. Using a platform called PRISM, researchers from Dana-Farber and the Broad Institute have tested 4,100 drugs against 578 laboratory-cultured cancer cell models. PRISM is a multiplexed method to efficiently evaluate the effects of drugs on pools of cancer cell lines at an unprecedented scale. The scientists say the experiment is among the largest cell line screens ever performed.
“Unexpectedly, more than 100 non-oncology drugs killed multiple cancer cell lines, making them attractive repurposing candidates,” said the researchers, led by Steven Corsello, MD, of Dana-Farber, and Todd Golub, MD, who, in addition to his Dana-Farber role, directs the Cancer Program at the Broad Institute.
The scientists are working to confirm their preliminary results and test the drugs in preclinical models. “Importantly, this approach is expected to enable rapid initiation of clinical trials, dramatically accelerating patient access to potential new therapies,” said the investigators.
The research (Control Number 17-A-4025-AACR) will be presented on Tuesday, April 4, from 1:00 p.m. to 5:00 p.m.