MD Anderson Research Highlights for December 19, 2022

Insights into immunotherapy treatments and side effects, targeted therapy advances, new oncology provider training and an international drug discovery resource

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 cell cycle checkpoint inhibitor with potential therapeutic effects in an ovarian cancer subtype, a telementoring program for French-speaking oncology providers in Africa, insights into the relationship between obesity and immunotherapy side effects, updates to the world’s largest cancer drug discovery knowledgebase, improvements to treatment response by blocking the EGFR pathway, and a novel noninvasive diagnostic test for immunotherapy-related kidney injury.  

WEE1 inhibitor yields promising results in CCNE1-amplified epithelial ovarian cancer 
Cyclin E1 is a kinase involved in regulating cell division, and its corresponding gene CCNE1 is amplified in multiple tumor types. The WEE1 kinase is a cell cycle checkpoint that allows time for DNA damage repair to avoid death in cells with CCNE1 overexpression, resulting in unchecked growth. The WEE1 inhibitor adavosertib releases these checkpoints and forces damaged cells to undergo cell death. Preclinical models show CCNE1 amplification sensitizes cancer cells to adavosertib, highlighting a possible connection. In a Phase II study led by Siqing Fu, M.D., Ph.D., researchers investigated CCNE1 amplification as a possible biomarker of response to adavosertib. In 30 patients with CCNE1 amplification, adavosertib achieved a median overall survival (OS) of 9.9 months and objective response rate (ORR) of 27%. Interestingly, in 14 patients with CCNE1-amplified epithelial ovarian cancer, the ORR was 36% and median OS was 14.9 months, meriting further study in this specific population. Learn more in the Journal of Clinical Oncology.

Telementoring and e-learning in underserved French-speaking African countries improves patient care
The African continent carries a high share of the global cancer burden, especially for breast cancer and preventable cervical cancer. This is due, in part, to a shortage of well-trained oncology workers in remote areas. MD Anderson has successfully used the Project ECHO telementoring program to share knowledge and evidence-based practices among providers in Africa, but existing programs have only been conducted in English. To increase participation from French-speaking providers, Fokom Domgue, M.D., Sanjay Shete, Ph.D., and colleagues launched the Francophone Africa Women’s Cancer ECHO in Feb. 2022. The initiative provides monthly sessions with global providers and has increased participation from French-speaking providers in 15 African countries. Results show that participants enjoy learning with their peers, developing additional clinical expertise and increasing their ability to offer more comprehensive care to improve the overall quality of care for patients in underserved settings. Learn more in The Lancet Global Health.

Study offers insights into relationship between body mass index and immunotherapy safety profile 
Obesity is associated with poor patient outcomes across multiple tumor types. However, analyses of patients with metastatic melanoma, non-small cell lung cancer or kidney carcinoma treated with immune checkpoint inhibitors paradoxically show that obesity correlates with improved survival. To determine if obesity may also be linked with immunotherapy side effects, researchers led by Jennifer McQuade, M.D., used existing clinical trial data to investigate the relationship between body mass index (BMI) and immune-related adverse events (irAEs). The study included 3,772 patients across 14 trials and eight tumor types, treated with weight-based nivolumab with or without ipilimumab. Obesity was associated with a higher incidence of mild or moderate irAEs compared to normal or underweight BMI, but there was no correlation for more serious grade 3 or 4 adverse events. This study provides further insights into the relationship between BMI and the safety profile of checkpoint inhibitors. Learn more in JAMA Oncology.

MD Anderson hosts cancer drug discovery resource to facilitate drug development efforts worldwide
To expand the impact of research beyond its walls, MD Anderson is now home to the canSAR knowledgebase, the world’s largest public cancer drug discovery resource. Through institutional data science efforts, MD Anderson is supporting canSAR and offering it as a free resource for the international research community to empower cancer drug discovery worldwide. Used by hundreds of thousands of researchers globally, the knowledgebase integrates billions of experimental measures across disciplines that inform drug discovery — including chemistry, systems biology and clinical data — and employs a unique artificial intelligence (AI) system to support decision-making in early drug discovery and translational biology research. In a new publication, Bissan Al-Lazikani, Ph.D., and colleagues report on important updates to the knowledgebase, which offer continued support and improvements to better enable drug discovery efforts. Learn more about canSAR, its content and latest updates in Nucleic Acids Research.

EGFR-targeted therapy improves antitumor response in inflammatory breast cancer by altering tumor microenvironment
Inflammatory breast cancer (IBC) is unresponsive to conventional treatments due in part to an immunosuppressive tumor microenvironment (TME). Researchers led by Xiaoping Wang, Ph.D., and Naoto T. Ueno, M.D., Ph.D., previously established the combination of anti-EGFR antibody panitumumab and neoadjuvant chemotherapy as a viable treatment strategy for patients with IBC, resulting in the highest known pathological complete response rate (42%). In a new study, the researchers sought to build upon this work and uncover the mechanisms regulating responses to this combination therapy. Using humanized IBC mouse models, they demonstrated that EGFR-targeted therapy remodels the TME to be more receptive to immune checkpoint inhibitors, improving the antitumor response of immunotherapy. This highlights the therapeutic potential of suppressing the EGFR pathway as a means of improving responses for patients with IBC. Learn more in Science Advances.  

Tertiary lymphoid structure signatures used to develop non-invasive diagnostic tool for immunotherapy-related acute interstitial nephritis 
Immune checkpoint inhibitor (ICI) therapy can sometimes have serious immune-related adverse events (irAEs), such as acute interstitial nephritis (AIN), an inflammation of the kidney that can lead to renal failure. Currently, invasive biopsies are the only way to diagnose AIN, highlighting a need to understand its pathophysiology and develop non-invasive diagnostic tests. Tertiary lymphoid structures (TLSs) are clusters of immune cells that arise in response to chronic inflammation, and their presence is associated with improved ICI responses. Collaborative research led by Jamie Lin, M.D., and Cassian Yee, M.D., examined kidney tissue biopsies of patients who developed acute kidney injuries from ICI therapy and identified specific TLS gene signatures associated with ICI-AIN compared to other causes of kidney injury. The ICI-AIN group had increased expression of genes associated with pro-inflammatory cytokines and immune cells. The researchers correlated those results with paired urine specimens and determined that urine testing can be used to detect AIN and manage this immunotherapy side effect. Learn more in JCI Insight.

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