MD Anderson Research Highlights for November 17, 2021

Featuring discoveries in DNA damage response, immunotherapy combinations, radiosensitizers and leukemia treatment approaches

The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into recently published studies in basic, translational and clinical cancer research from MD Anderson experts. Current advances include discovering a new protein that regulates the DNA damage response, evaluating immunotherapy plus cryoablation to treat metastatic kidney cancer, identifying radiosensitizer targets to improve radiation therapy response, personalizing treatment intensity for acute myeloid leukemia, and identifying T cell features that play a role in response and resistance to cell therapy in leukemia.

SPINDOC protein interacts with PARP1 to regulate DNA damage response

The SPINDOC protein was discovered as part of a complex that reads epigenetic marks on histones to regulate gene expression. In an effort to further characterize and better understand the role of SPINDOC, researchers led by Fen Yang, Ph.D., and Mark Bedford, Ph.D., unexpectedly discovered that the protein also interacts with PARP1 to control key DNA damage response processes. In the event of DNA damage, SPINDOC levels are elevated and recruited with PARP1 to the DNA lesions. At the site of DNA damage, PARP1 adds chemical modifications to a number of proteins — a process called PARylation — to recruit and stimulate factors needed to repair the DNA. The researchers demonstrated that loss of SPINDOC led to a decrease in PARylation and a hypersensitivity to DNA damage, suggesting this protein plays an important role in regulating the DNA damage response. Learn more in Nature Communications.

Checkpoint blockade plus cryoablation stimulates immune remodeling in advanced kidney cancer

Cryoablation — a treatment designed to kill cancer cells with extreme cold — in combination with immune checkpoint inhibitors stimulated anti-tumor immune responses in preclinical studies. To examine whether this combination is safe and feasible for patients, Matthew Campbell, M.D., and Padmanee Sharma, M.D., Ph.D., led a pilot clinical study in patients with metastatic renal cell carcinoma (RCC), including 18 with clear cell and 11 with non-clear cell histology. Patients received the anti-CTLA-4 therapy tremelimumab with or without cryoablation. Immune-mediated toxicities of grade 3 or greater were observed in 55.2% of patients, in keeping with previous studies of immune checkpoint blockade in RCC. Although clinical responses were limited, immune analyses of pre- and post-treatment samples revealed that cryoablation increased immune cell infiltration and the presence of tertiary lymphoid structures in clear cell RCC. The findings suggest this combination is feasible and can stimulate favorable changes in the immune microenvironment in certain patients with metastatic RCC. Learn more in Nature Communications.

Study identifies CBP/p300 as radiosensitizer targets in cancer with certain genetic mutations

Radiation therapy is a key component of many cancer treatment strategies, so improving responses to radiation could benefit many patients. Radiosensitizers can make tumors more susceptible to radiation, but available radiosensitizers are limited and associated with significant toxicities. In an effort to identify new targets for radiosensitizers, Curtis Pickering, Ph.D., and colleagues conducted a genetic screen in preclinical models of head and neck cancer treated with radiation. They discovered that targeting CBP and p300 increased radiation sensitivity, but only in tumors harboring mutations in the corresponding genes (CREBBP and EP300). Mutations in these genes actually drive resistance to radiation — patients with mutations have poorer outcomes from radiation therapy — but blocking specific activities of the proteins in mutant tumors rendered cells susceptible to radiation. These findings suggest CBP and p300 may be viable radiosensitizer targets in patients with specific genetic mutations. Learn more in Nature Communications.

Predicting early mortality in patients with AML receiving intensive vs. low-intensity chemotherapy 

In addition to existing intensive chemotherapies for newly diagnosed acute myeloid leukemia (AML), low-intensity therapies have been recently developed. To help determine which therapeutic options might be best for each patient, researchers led by Koji Sasaki, M.D., Ph.D., and Hagop Kantarjian, M.D., conducted a retrospective analysis of 3,728 patients with newly diagnosed AML treated with intensive chemotherapy. They created a risk classification model by identifying risk factors for early (4-week) mortality after starting chemotherapy that included tumor burden, leukemia karyotype, existing infections and age, and then applied this model to 1,306 patients treated with low-intensity therapies. Early mortality rates in the very-high-risk groups were markedly different between treatment intensities. Following intensive chemotherapy, early mortality rates were 2%, 14%, and 50% in the low-, high-, and very-high-risk group, respectively, compared with 3%, 9%, and 20% following low-intensity therapies. Basing treatment intensity on this model could reduce mortality during AML therapy and improve patients’ long-term survival. Learn more in the American Journal of Hematology.

Study identifies T cell features associated with response and resistance to leukemia cell therapy

Donor lymphocyte infusion (DLI) is an established cell therapy for patients with relapsed leukemia, but is ineffective in some patients. To better understand the dynamics behind responses, Pavan Bachireddy, M.D., and colleagues performed comprehensive molecular profiling of >94,500 individual bone marrow-derived T cells taken pre- and post-DLI in 16 patients. The team developed novel computational approaches to analyze the various data types across multiple timepoints. In DLI responders, the researchers identified a dysfunctional ‘exhausted’ T cell phenotype at baseline, followed by rapid, durable expansion of progenitor T cell populations post-treatment. Conversely, T cells in non-responders displayed a variety of dysfunctional traits. Surprisingly, the expanding, progenitor T cells did not derive from the DLI product; rather, they expanded from pre-existing populations. The findings provide new insight into the dynamics of anti-leukemia T cells and offer new approaches for analyzing single-cell profiling data over time. Learn more in Cell Reports.

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