MD Anderson Research Highlights for April 12, 2024

Featuring strategies to overcome treatment resistance, targets for ovarian and BRAF-mutated cancers, and a novel risk prediction tool for hereditary cancers

MD Anderson News Release April 12, 2024

The University of Texas MD Anderson Cancer Center’s Research Highlights showcases the latest breakthroughs in cancer care, research and prevention. These advances are made possible through seamless collaboration between MD Anderson’s world-leading clinicians and scientists, bringing discoveries from the lab to the clinic and back.

Recent developments at MD Anderson offer insights into a combination strategy to improve immunotherapy responses, promising trial results for patients with tumors harboring BRAF mutations, a maintenance strategy for patients with acute myeloid leukemia following chemotherapy, a strategy to overcome PARP inhibitor resistance in patients with BRCA1-deficient cancers, insights into Phase III trial subgroup analyses, a promising therapeutic target for homologous recombination-proficient epithelial ovarian cancers, and a new model to predict cancer risk for patients with Li-Fraumeni syndrome and other hereditary cancers.

Combination strategy remodels tumor microenvironment to improve anti-tumor response
Inducible T cell costimulator (ICOS) is a T cell-specific protein, and ICOS agonists enhance the efficacy of CTLA-4 immune checkpoint blockade. Previous studies have shown that, while ICOS pathway activation in combination with CTLA-4 blockade relies on a T cell-mediated response, CD8+ T cells only partially contributes to tumor rejection. In a new study from the James P. Allison Institute, led by Naveen Sharma, Ph.D., and James Allison, Ph.D., researchers hypothesized that tumor-associated macrophages (TAMs) may play a role in combination therapy activity. Using high-dimensional profiling, they analyzed changes in immune cells that infiltrate tumors and demonstrated that TAMs play a crucial role in remodeling the tumor microenvironment. ICOS co-stimulation combined with anti-CTLA-4 immunotherapy remodeled immunosuppressive TAMs into anti-tumor TAMs in a positive feedback loop with intratumoral effector T cells, suggesting this strategy could improve treatment outcomes. The study recommends further examination of the role of TAMs in immunotherapy treatment efficacy. Learn more in the Journal of Experimental Medicine.

Rechallenge therapy with RAF inhibitors shows promise in BRAF-aberrant cancers
Treating patients with a different RAF inhibitor after disease progression, a process known as rechallenging, has demonstrated anti-tumor efficacy in melanoma, but little is known about rechallenging the RAF pathway in other solid tumors. In the RE-RAFFLE study, led by Blessie Nelson, M.B.B.S., 44 patients with multiple tumors harboring RAF alterations were rechallenged with a second RAF inhibitor. Patients had an overall response rate of 18.1% and a clinical benefit rate of 54.5%, with more than 30% of patients having durable responses lasting longer than six months. However, acquired resistance remained a significant challenge. The researchers noted that future prospective studies are needed to further validate and expand rechallenge targeted therapy options. Learn more in Molecular Cancer.  

Low-dose azacitidine plus venetoclax suitable as maintenance therapy for AML patients following chemotherapy
A majority of patients with acute myeloid leukemia (AML) experience relapse when they are unable to complete standard consolidation options or receive an allogeneic stem cell transplant. In a Phase II clinical trial led by Tapan Kadia, M.D., and Alexandre Bazinet, M.D., researchers investigated a maintenance therapy regimen consisting of the BCL-2 inhibitor venetoclax and a low dose of azacitidine. The trial enrolled 35 patients who were in remission following intensive (cohort 1) or low-intensity chemotherapy (cohort 2). Median relapse-free survival – the study’s primary outcome – was not yet reached in cohort 1 and was 30.3 months for cohort 2, indicating encouraging responses. The two-year relapse-free survival rate for all patients was 65%, and all side effects were manageable. The results suggest that the combination therapy is a viable maintenance strategy for this patient population. Learn more in The Lancet Haematology.

GPX4 and PARP co-inhibition may boost PARP inhibitor effectiveness in BRCA1-deficient cancers 
Many BRCA1-deficient cancers develop resistance to Poly (ADP-ribose) polymerase (PARP) inhibitor monotherapy, highlighting a need to understand the underlying mechanisms to improve treatment outcomes. In a new study led by Boyi Gan, Ph.D., researchers showed that BRCA1-deficient cancers have a vulnerability that can be exploited using a combination treatment that makes PARP inhibition more effective. They found that BRCA1 has a role in regulating ferroptosis, a type of cell death triggered by lipid peroxidation. In BRCA1-proficient cancers, the tumor’s adaptive response to PARP inhibition negates its ferroptosis-inducing effects, but BRCA1 deficiency makes tumors vulnerable to ferroptosis induced by GPX4 and PARP co-inhibition. In preclinical models, xenograft tumors from BRCA1-mutated breast cancer patients with PARP inhibitor resistance were highly sensitive to this combination, supporting this co-inhibition as a therapeutic strategy. Learn more in Cancer Discovery.  

Study suggests subgroup analyses of Phase III oncology trials need improvement
Phase III randomized controlled trials (RCTs) play a crucial role in evaluating the effectiveness of new cancer treatments. Subgroup analyses often are performed to investigate treatment differences among patient groups in the trial. To assess the reliability of claims about different treatment effects in oncology trials, researchers led by Alexander Sherry, M.D., Pavlos Msaouel, M.D., Ph.D., and Ethan Ludmir, M.D., examined 379 published Phase III RCTs with subgroup analyses. The researchers found that 43% of trials had incomplete visual elements on the forest plots needed for interpretation, and the credibility of claims regarding differential treatment effects was assessed as low or very low in 93% of instances. This underscores the importance of improving the quality of subgroup analyses in Phase III cancer trials and carefully interpreting current subgroup findings in ongoing trials. Learn more in JAMA Network Open.

Targeting branched N-glycans and fucosylation sensitizes ovarian tumors to immune checkpoint blockade
High-grade serious ovarian cancer accounts for more than 70% of epithelial ovarian cancers, which are the most lethal gynecologic cancer in the U.S. About half of these cancers harbor defects in the homologous recombination DNA repair pathway, making them susceptible to treatment with PARP inhibitors. However, treatment options remain limited for those without these defects. To address this, Rugang Zhang, Ph.D., and colleagues demonstrated a potential vulnerability in these cancers that sensitizes them to immune checkpoint inhibitors. Aberrant glycosylation – changes in the way sugar molecules are attached to proteins – can help epithelial ovarian cancers evade detection. One type of protein, a branched N-glycan, allows specific cancers to evade CD8+ T cell response. Inhibiting these branched N-glycans in preclinical models sensitized the tumors to immune checkpoint inhibitors. These findings demonstrate that branched N-glycans could be a promising therapeutic target in homologous recombination-proficient epithelial ovarian cancers. Learn more in Nature Communications.

Novel model uses clinical data to predict cancer risk for Li-Fraumeni syndrome
Li-Fraumeni syndrome (LFS) is a hereditary disorder characterized by germline mutations in the TP53 tumor suppressor gene, increasing a patient’s risk for various cancer types. There are limited risk prediction models for LFS because research datasets take decades to be completed for model development purposes. These datasets, however, do not reflect model performance in clinical settings since genetic counselors often must base their risk assessments on single counseling visits and incomplete family history. To address this, researchers led by Wenyi Wang, Ph.D., and Banu Arun, M.D., trained and validated new risk prediction models by using clinical data from 3,297 patients across 124 families. Their models performed well with patients with either primary or multiple primary cancers who underwent genetic counseling sessions. The researchers developed primary cancer risk and recurring event models for LFS, which performed well in predicting TP53 mutations in untested patients. The models also compared favorably to other validation studies using research cohorts. These models stress the importance of using clinical data and improving data collection within clinic visits to potentially improve care for patients with hereditary cancers. Learn more in the Journal of Clinical Oncology.

Awards and honors

MD Anderson at AACR 2024
Read below for highlights from MD Anderson at the American Association for Cancer Research (AACR) Annual Meeting 2024. More information can be found at MDAnderson.org/AACR.

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