Scientists from Dana-Farber Cancer Institute are presenting results of basic and clinical investigations at the American Association for Cancer Research (AACR) Annual Meeting on April 14th-18th in Chicago, IL. Many Dana-Farber faculty will be making presentations through plenary and education session, poster and abstracts presentations, etc. Selected highlights include:
Reversing drug resistance in metastatic breast cancer
Abstract 4952 A Therapeutic “About Face” – Reversing Drug Resistance
Room W190 – McCormick Place West (Level1)
Tuesday, April 17, 3 pm – 5 pm
Utthara Nayar, PhD
Researchers used whole exome sequencing to identify resistance mechanisms in patients with estrogen-receptor positive (ER+) metastatic breast cancer who had developed resistance to aromatase inhibitors, tamoxifen, and fulvestrant. Resistant ER+ cancer is the most common cause of breast cancer death. In tumors from four patients, it was found that activating mutations in epidermal growth factor receptor 2 (HER2) had been acquired during treatment with ER-directed drug therapy. These mutations represent “a distinct mechanism of resistance to ER-directed therapies,” say the researchers, led by Utthara Nayar, PhD, Ofir Cohen, PhD, and Nikhil Wagle, MD, who showed in lab experiments that the mutations conferred estrogen independence as well as resistance to tamoxifen, fulvestrant, and the CDK4/6 inhibitor palbociclib. Furthermore, the investigators found that resistance caused by the four mutations was overcome by combining ER-directed therapy with neratinib, an irreversible HER2 kinase inhibitor, “suggesting a novel effective treatment strategy in these patients.”
Targeting resistance mechanisms in Ewing sarcoma
Abstract 1629 in Pediatric Cancer: Poster Discussion
Room S402 – McCormick Place South (Level 4)
Sunday, April 15, 3 pm to 4 pm
Lillian Guenther MD
A dearth of new targeted drugs for the aggressive pediatric bone tumor, Ewing sarcoma, led Dana-Farber scientists to study the CDK4/6 cell signaling pathway, on which the sarcoma has been found to depend. The researchers identified a gene, IGF1R, which, when overexpressed, allows Ewing sarcoma cells to escape from the CDK4/6 inhibitors palbociclib and ribociclib. Using the CRISPR gene editing tool, the investigators found that knocking out the IGF1R gene neutralized the resistance mechanism, rendering the Ewing sarcoma cells sensitive to CDK4/6 inhibitors.
Next, the scientists tested the CDK4/6 inhibitor ribociclib together with an experimental IGF1R inhibitor in a mouse model implanted with a Ewing sarcoma tumor, and found prolonged survival and decreased tumor volumes with the combination. The results, the researchers say, suggests “that dual targeting of CDK4/6 and IGF1R provides a candidate synergistic drug combination for this disease.”
Vaccine generates neoepitope-specific T cell responses in glioblastoma
Abstract 5631 Vaccines 2 Poster Session Section 29
Wednesday, April 18 8 am – 12 noon
David Reardon, MD
A small study shows for the first time that immune T cells with specificity for glioblastomas can penetrate into these highly malignant brain tumors and reprogram the tumor microenvironment to be more favorable for an immune response. Dana-Farber investigators tested a personal neoantigen vaccine, which is made individually from each patient’s tumor to target proteins called neoantigens produced by mutations in the cancer cells; the neoantigens are not present on normal cells.
The vaccine was administered in a phase 1/1b trial to eight patients with newly diagnosed glioblastoma following surgery and radiation therapy. Only mild side effects resulted from the vaccine injections. Overall survival was 16.8 months. Three patients who required dexamethasone during vaccine priming failed to generate immune responses. However, two patients who did not receive dexamethasone generated robust immune responses against the neoantigens in the vaccine. Increased numbers of tumor-infiltrating CD4 and CD8 T cells were detected in these two patients.
“To our knowledge, we provide the first evidence that tumor-specific T cells can traffic from the periphery into glioblastoma tumors and that neoantigen-targeting vaccines can favorably alter the tumor immune milieu of glioblastoma,” the scientists say. “Individualized, multi-neoepitope vaccination is feasible, safe, and generates neoantigen-specific T cell responses in the periphery and intracranial tumors of patients with glioblastoma.”
Personalized Neoantigen Vaccines
N Hall B (Plenary Hall) - McCormick Place North (Level 3)
April 15, 2018, 1-2:45 p.m.
Catherine Wu, MD, a physician at the Dana-Farber Cancer Institute and a Parker Institute investigator, chairs this symposium on personalized cancer vaccines, an exciting area of emerging research in immuno-oncology. Dr. Wu will discuss designing and improving personalized cancer vaccines.
Chromatin Remodeling Machines in Cancer
N Hall B – McCormick Place North (Level 3)
April 18, 2018, 8:55 am – 9:20 am
Cigall Kadoch, PhD, will address this plenary session - Impact of Cancer Genomics on Cancer Susceptibility and Therapeutic Response on Chromatin Remodeling Machines in Cancer: New Mechanisms and Therapeutic Response.