MD Anderson Research Highlights for October 19, 2022

Featuring an approach to overcome PARP inhibitor resistance, insights into the “obesity paradox” in advanced melanoma, and mechanisms driving cancer progression and metastasis

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 a combination approach to overcome PARP inhibitor resistance in breast and ovarian cancers, a deeper understanding of STAT3 mutations as drivers of disease progression, insights into the “obesity paradox” in men with advanced melanoma, a prognostic model for rapidly-progressing vestibular schwannoma, and a role for cellular trafficking proteins in creating a metastasis-promoting lung cancer microenvironment.  

Combination targeted therapy may overcome PARP inhibitor resistance in breast and ovarian cancers 
Targeted therapy with PARP inhibitors is commonly used to treat breast and ovarian cancers, but their efficacy is limited due to acquired resistance. In a new study, Yu-Yi Chu, Ph.D., Dihua Yu, M.D., Ph.D., and colleagues studied tumor biospecimens to understand the mechanisms of resistance and to identify biomarkers that can predict treatment response. They identified ALK as a biomarker that promotes DNA repair in cancer cells and drives PARP inhibitor resistance, uncovering a crucial step in understanding how membrane receptors can alter the DNA damage response pathway. Their findings suggest combining PARP inhibitors with selective ALK inhibitors already approved by the Food and Drug Administration could be an effective therapeutic strategy for treatment-resistant tumors. Learn more in Nature Cancer.

Stability of STAT3 mutant proteins affects DNA binding and disease progression 
STAT3 is crucial in multiple signaling pathways involved in cell proliferation and survival as well as host immunity. STAT3 mutations, particularly in the protein’s DNA-binding domain (DBD) and Src-homology 2 domain (SH2D), cause immunodeficiency and cancer, but it is unclear how these mutations alter STAT3 function and contribute to disease. Researchers led by Moses Kasembeli, Ph.D., and David Tweardy, M.D., characterized how loss-of-function (LOF) mutations that cause immunodeficiency or gain-of-function (GOF) mutations that cause cancer affect STAT3 protein stability and DNA-binding activity. As expected, mutations in the DBD impacted STAT3’s DNA-binding activity but not protein stability. In the SH2D, LOF mutations reduced conformational stability, leading to decreased activity at multiple steps in STAT3 signaling, including DNA binding. In contrast, cancer-causing SH2D GOF mutants showed increased protein stability and DNA binding. Treatment with a small-molecule STAT3 inhibitor targeting the SH2D blocked cell proliferation driven by GOF mutations, highlighting potential therapeutic opportunities. These findings illustrate the importance of STAT3 protein stability for its DNA binding activity and its relationship to health and disease. Learn more in Blood

Downregulation of metabolic pathways contributes to “obesity paradox” in advanced melanoma
Previous research led by Jennifer McQuade, M.D., found that obesity is associated with longer survival for men with metastatic melanoma who were treated with immune checkpoint inhibitors and BRAF-targeted therapies. To further investigate this “obesity paradox,” Andrew Hahn, M.D., McQuade and colleagues assessed the integrated molecular, metabolic and immune profiles of tumors and the gut microbiome in multiple samples from high- and low-BMI patient cohorts. The researchers found no differences in somatic DNA alterations or in the gut microbiome. However, multiple metabolic pathways, including oxidative phosphorylation and glycolysis, were downregulated in melanoma tumors from overweight/obese patients. Though the exact mechanism behind this association remains unclear, these results provide further insight into the variability of treatment responses. Learn more in Clinical Cancer Research.

Immune signature profile provides prognostic model in rapidly progressing vestibular schwannomas   
Vestibular schwannomas (VS) are tumors on the main nerve from the inner ear to the brain. Complete VS removal is not always safely possible, resulting in incomplete resection. Variable rates of disease progression following incomplete resection can make it difficult to determine appropriate treatment strategies. Understanding the immune signature associated with rapid VS progression could provide a useful prognostic tool for determining risk and selecting treatment. Researchers led by Moran Amit, M.D., Ph.D., Tongxin Xie, M.D., Ph.D., Frederico Gleber-Netto, Ph.D., Patrick Hunt, Ph.D., and Franco DeMonte, M.D., characterized the immune microenvironment in 17 patients, highlighting key differences in signal pathways between rapidly progressing and slowly to non-progressing VS. Viral response pathways were enriched in those with rapid VS progression, suggesting an immune etiology with possible viral origins. These findings provide further understanding of disease progression following incomplete resection and open the door to the possibilities for immunotherapeutic intervention. Learn more in the Journal of Experimental & Clinical Cancer Research.

Study identifies new trafficking proteins involved in lung cancer metastasis  
Non-small cell lung cancer has a high probability of metastasizing, highlighting a need to understand the underlying mechanisms that lead to its aggressive spread. Researchers led by Rakhee Bajaj, Ph.D., and Don Gibbons, M.D., Ph.D., built upon previous work implicating the Impad1 protein as a driver of metastasis. Impad1 is found in the Golgi apparatus, a cellular organelle involved in protein transport. In this study, the researchers discovered that Impad1 interacts with a trafficking protein, Syt11, to alter the Golgi apparatus and change vesicular trafficking in a way that creates a metastasis-promoting microenvironment. Inhibiting Impad1 or Syt11 reversed these effects, suggesting these proteins play an important role in regulating the tumor microenvironment and underscoring their potential as therapeutic targets. Learn more in Cell Reports.

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Immunofluorescent staining of Edu (green) and DAPI (blue) to indicate the PARPi-resistant TNBC cancer cells in the S phase. Image courtesy of Yu-Yi Chu, Ph.D.