MD Anderson Research Highlights for August 10, 2022

Featuring CRISPR screens to enhance chemotherapy benefits, targeted therapies for kidney and colorectal cancer, and a novel engineered TIL therapy for ovarian cancer

The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into recent basic, translational and clinical cancer research from MD Anderson experts Current advances include using a CRISPR screen to identify targets for improved chemotherapy responses, the potential of glutaminase inhibitors as novel treatments in renal cell carcinoma, engineered tumor-infiltrating lymphocytes to overcome immune suppression in ovarian cancer, oncolytic viruses to improve responses in glioblastoma, combination therapy options for KRAS/NRAS-mutant colorectal cancer, and a new treatment target for a subtype of myelodysplastic syndromes.

CRISPR screen identifies new target to enhance benefits from certain chemotherapies

During DNA replication, topoisomerase proteins (TOPs) play the critical role of making temporary DNA-strand breaks so they can be untangled and made accessible to the replication machinery. Some chemotherapies, such as camptothecin, work by trapping TOPs on the DNA, causing sustained breaks and cell death. The TDP1 protein can help repair this damage, but it is not clear what other players may be involved in this process. A new study led by Huimin Zhang, Ph.D., Yun Xiong, Ph.D., and Junjie Chen, Ph.D., used a whole-genome CRISPR screen to identify MUS81 as a key protein in repairing damage from topoisomerase 1 (TOP1) in the absence of TDP1. They clarified the mechanism for MUS81’s activity and showed that loss of both TDP1 and MUS81 enhanced cancer cell sensitivity to camptothecin. These findings suggest that MUS81 could be an alternate target to improve activity of certain cancer therapies. Learn more in Nature Communications.

Drug combination improves progression-free survival in patients with renal cell carcinoma

Renal cell carcinoma (RCC) tumors generally display specific genetic alterations that cause cancer cells to increase metabolism of glutamine. Dual targeting of glucose and glutamine metabolism by the mTOR inhibitor everolimus, plus the glutaminase inhibitor telaglenastat, showed preclinical synergistic anticancer effects. The Phase II ENTRATA study, led by Nizar Tannir, M.D., enrolled 69 patients with a median of three prior lines of therapy for advanced metastatic disease including 100% with two or more prior tyrosine kinase inhibitors (TKIs), and 88% with checkpoint inhibitors. At median follow-up of 7.5 months, median progression-free survival (PFS) was 3.8 months for the combination versus 1.9 months for the placebo. The results from this study showed that telaglenastat plus everolimus demonstrated improvement in PFS for heavily pretreated RCC patients and warrants further assessment of glutaminase inhibitors as potential novel treatments. Read more in Clinical Cancer Research.

Engineered TIL therapies resistant to TGF-β immune suppression in pre-clinical study

Higher levels of tumor-infiltrating T cells in ovarian cancer are correlated with improved patient survival, suggesting these T cells are capable of mounting an anti-tumor immune response. However, immune suppression from signaling in the tumor microenvironment can dampen this response. A new study from Samantha Fix, Ph.D., Chantale Bernatchez, Ph.D.Amir Jazaeri, M.D., and their colleagues reports the successful development of genetically engineered tumor-infiltrating lymphocytes (TILs) that are resistant to TGF-β, a major immunosuppressive signal. Their methods build upon previous work to optimize expansion of isolated TILs in culture. Using CRISPR/Cas9 gene editing, the researchers removed the gene encoding TGF-β receptor 2 (TGFBR2) in isolated TILs prior to expansion. In pre-clinical studies, these engineered TILs had enhanced cell-killing ability in the presence of TGF-β compared to controls. The study suggests this approach may provide opportunities to improve TIL therapies for ovarian cancers and other solid tumors. Learn more in the Journal for ImmunoTherapy of Cancer.

Oncolytic virus plus targeted therapy effective against glioblastoma in pre-clinical study

Engineered oncolytic viruses can provoke anti-tumor immune responses in glioblastoma, as shown by a 20% response rate in a phase I MD Anderson study. However, immunosuppressive signals in the tumor microenvironment can limit the efficacy of these therapies. Researchers led by Teresa Nguyen, Ph.D., Candelaria Gomez-Manzano, M.D., and Juan Fueyo, M.D., demonstrated that an oncolytic virus carrying a T cell activator (Delta-24-RGDOX ) combined with targeted inhibitors of IDO – a suppressive immune signal – can effectively reshape the microenvironment to enhance anti-tumor immune responses. Delta-24-RGDOX alone led to activation of IDO pathways but adding IDO inhibitors increased anti-tumor T cells and decreased suppressive immune cells. The combination also improved the survival of laboratory glioma models, suggesting this therapeutic approach warrants further clinical evaluation for patients with glioblastoma. Learn more in the Journal for ImmunoTherapy of Cancer.

Targeted therapy combination shows early activity in KRAS/NRAS-mutant CRCs

Roughly 45% of all colorectal cancers (CRCs) harbor KRAS/NRAS mutations, and these cancers do not respond to currently approved targeted therapies. Emerging KRAS G12C inhibitors are promising, but KRAS G12C mutations are found in a small fraction of CRCs. To offer better treatment options, scientists have proposed targeting multiple signaling pathways downstream of KRAS/NRAS. In a new study led by Alexey Sorokin, Ph.D., Michael Lee, M.D., and Scott Kopetz, M.D., Ph.D., researchers demonstrated that combining targeted therapies against MEK (binimetinib) and CDK4/6 (palbociclib) resulted in encouraging signs of anti-tumor activity in a co-clinical trial. In 18 patient-derived xenograft (PDX) models, 60% of tumors responded to the combination therapy and researchers were able to identify biomarkers of response and mechanisms for therapeutic resistance. In the corresponding safety lead-in to a Phase II study of six patients with metastatic CRC and KRAS/NRAS mutations, the combination was well-tolerated and achieved a response in one patient. These early data highlight the value of this co-clinical trial platform and the potential for this combination therapy. Learn more in Cancer Research.

Study uncovers new treatment target in MDS subtype with specific mutations

Myelodysplastic syndromes with ringed sideroblasts (MDS-RS) are a subtype of MDS marked by the accumulation of immature red blood cells (sideroblasts) and significant anemia. Mutations in SF3B1 are found in approximately 20% of patients with MDS-RS, but it has not been fully understood how these mutations disrupt the differentiation process of red blood cells. A new study led by Vera Adema, Ph.D., and Simona Colla, Ph.D., used single-cell gene expression profiling on primary MDS-RS samples to discover that mutant SF3B1 arrests cellular differentiation, leading to activation of the EIF2AK1 signaling pathway to maintain the cells’ survival in response to heme deficiency. The researchers validated these findings in laboratory models and showed that treatment with the hypomethylating agent 5-azacitidine could overcome EIF2AK1 signaling and enable red blood cell production. These data support the further development of EIF2AK1 inhibitors to overcome the dependency on blood transfusions in patients with SF3B1-mutant MDS-RS. Learn more in Blood Cancer Discovery.

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