MD Anderson Research Highlights for April 13, 2022

Featuring advances in immunotherapy combinations, quality of life after breast cancer treatment, liver cancer subtypes, bladder cancer targets, immune-related side effects and p53 pathway regulation

MD Anderson News Release April 13, 2022

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. Studies include clinical advances with immunotherapy combinations and quality of life for breast cancer patients plus molecular subtypes for liver cancer, new treatment targets in bladder cancer, mechanisms driving immune-related side effects, and the effects of specific gene mutations on p53 activity.

Atezolizumab plus bevacizumab shows promise for neuroendocrine tumors
Recent developments in the treatment of advanced, well-differentiated neuroendocrine tumors (NETs) have produced limited responses, and immune checkpoint inhibitors alone have not been effective for patients with this rare cancer type. This single-arm clinical trial tested a combination therapy with the checkpoint inhibitor atezolizumab and the vascular endothelial growth factor (VEGF) inhibitor bevacizumab. The study, led by Daniel Halperin, M.D., enrolled patients with rare solid tumors, including 40 patients with advanced NETs. An objective response was observed in four of the 20 patients (20%) with pancreatic NETs, and the median progression-free survival (PFS) in this cohort was 14.9 months. In the cohort of 20 patients with extra-pancreatic NETs, three patients (15%) had an objective response and the PFS was 14.2 months. The results support exploring combination therapy further. Learn more in JAMA Oncology.

Consensus subtypes of hepatocellular carcinoma may improve treatment selection
Hepatocellular carcinoma (HCC) — the most common type of liver cancer — is a heterogeneous disease composed of different molecular subtypes. A better understanding of these subtypes, based on specific tumor alterations, could improve treatment selection, but there is no uniform system to stratify HCC subgroups. A research team led by Ju-Seog Lee, Ph.D., integrated 16 previously published HCC genomic signatures to identify five consensus subtypes significantly correlated with clinical outcomes. The team characterized the molecular features of each group and demonstrated these features were conserved in laboratory models. They developed a 100-gene signature to classify tumors into a subtype and identified potential blood biomarkers that could be used to stratify patients. These consensus subtypes provide a framework for preclinical studies to identify optimal therapeutic strategies, which could help with selecting more effective therapies for patients in the future. Learn more in Hepatology.

Loss of MTAP represents a targetable vulnerability in urothelial cancer
Immunotherapy and targeted therapies have improved outcomes for patients with urothelial carcinoma (UC) — the most common form of bladder cancer — but progress is needed to better treat resistant subtypes. Loss of chromosome region 9p21 is common and associated with poor prognosis. One of the genes within this region is MTAP, which encodes an essential metabolic enzyme, potentially creating a metabolic vulnerability. In preclinical and clinical studies, researchers led by Omar Alhalabi, M.D., Jianfeng Chen, M.D., Ph.D., Linghua Wang, M.D., Ph.D., and Jianjun Gao, M.D., Ph.D., demonstrated that pemetrexed — a chemotherapy targeting another complementary metabolic process — shows activity against MTAP-deficient UCs. Cell lines with MTAP loss had increased sensitivity to pemetrexed and, in a small prospective Phase II trial, pemetrexed resulted in a 43% overall response rate in patients with MTAP-deficient cancers. These results were confirmed in retrospective analyses of independent trials for UC and lung cancer, suggesting pemetrexed warrants further evaluation in patients with MTAP loss. Learn more in Nature Communications.

Study identifies factors driving arthritis following immunotherapy treatment
Immune checkpoint inhibitors offer profound responses but can cause immune-related side effects that can limit their benefits. Arthritis — the most common rheumatic immune-related side effect — can impair quality of life and disrupt treatments. Understanding the mechanisms driving this side effect could point to treatment approaches that would not blunt the anti-tumor immune response. Researchers led by Sang Kim, M.D., Ph.D., Yanshuo Chu, Ph.D., Linghua Wang, M.D., Ph.D., and Roza Nurieva, Ph.D., analyzed blood and/or joint fluid from 20 patients with arthritis caused by checkpoint inhibitors to determine associated molecular and cellular features. They discovered that interferon gamma (IFNg)-producing Th1/Tc1 cells play an important role in immunotherapy-induced arthritis. Further, they demonstrated that Th17 cells are enriched in arthritis after combined anti-CTLA-4/anti-PD-1 checkpoint inhibitor treatment and are involved in resistance to steroid therapies. These findings offer potential predictive biomarkers and therapeutic targets for immunotherapy-related arthritis. Learn more in Nature Communications.

Quality of life outcomes for early stage breast cancer patients examined
Women diagnosed with early stages of breast cancer are often given treatment choices, including breast conserving surgery with radiation therapy or mastectomy with or without breast reconstruction. Although other studies have shown comparable recurrence and survival rates between these treatment options, the long-term effects of the treatment decisions on patients’ quality of life have not been determined. A team led by Benjamin Smith, M.D., used a population-based cohort selected from the Texas Cancer Registry to determine patients’ satisfaction with their breasts 10 years after their cancer treatment. The study found that patient-reported satisfaction with their breasts was similar with either treatment, but psychosocial and sexual well-being were better in patients treated with breast-conserving surgery and radiation. These results can be used to inform treatment decision conversations between doctors and early stage breast cancer patients. Learn more in JAMA Surgery .

Doublet and triplet combinations with PD-1 inhibitors are safe and effective in advanced solid tumors
Doublet combinations targeting immune checkpoints have shown promising efficacy in patients with advanced solid tumors, but it is unclear if triplet combinations involving different classes of antitumor agents will be well tolerated and improve antitumor activity. In the multi-arm IOLite trial, Timothy Yap, M.B.B.S., Ph.D., and a team of researchers evaluated the recommended phase 2 doses, safety and efficacy of doublet and triplet combinations with PD-1 inhibitor dostarlimab in 55 patients with advanced solid tumors. Combinations included PARP inhibitor niraparib, with or without VEGF inhibitor bevacizumab, and carboplatin–paclitaxel chemotherapy, with or without bevacizumab. The results showed the combinations were safe and well tolerated with promising antitumor activity. These combinations are now being evaluated in Phase III studies for different cancers, including recurrent or primary advanced endometrial cancer and advanced non-mucinous epithelial ovarian cancer. Learn more in the Journal for ImmunoTherapy of Cancer.

JAK1 inhibition combined with IDO1 or PI3Kδ inhibition did not enhance immune activation
Although immune checkpoint blockade has demonstrated impressive anti-tumor activity, the tumor microenvironment (TME) may affect the therapeutic efficacy of combination treatments. In a Phase I multicenter study, Aung Naing, M.D., and a team of researchers evaluated the safety, tolerability, efficacy and translational effects on the tumor microenvironment of itacitinib (JAK1 inhibitor) in combination with epacadostat (IDO1 inhibitor) or parsaclisib (PI3Kδ inhibitor). The findings showed that JAK1 inhibition combined with either IDO1 or PI3Kδ inhibition led to some changes in the TME and plasma proteins with manageable adverse events, but the combinations demonstrated limited clinical activity or enhancement of immune activation in the tumor microenvironment. Further investigations are needed to fully evaluate combinations of targeted agents that may elicit antitumor immune responses. Learn more in the Journal for ImmunoTherapy of Cancer.

Targeting VEGF-2 with immunotherapy for advanced biliary tract cancer treatment has clinical benefits
Biliary tract cancers (also called bile duct cancers) are a rare group of cancers that have limited treatment options and a poor prognosis. This single-arm, Phase II clinical trial tested ramucirumab, a monoclonal antibody that inhibits vascular endothelial growth factor receptor-2 (VEGF-2), which contributes to biliary tract cancer growth through angiogenesis. The study enrolled 61 patients with advanced, unresectable, biliary tract cancers that progressed after treatment with gemcitabine-based chemotherapy. Milind Javle, M.D., Sunyoung S. Lee, M.D., Ph.D., and co-authors found that ramucirumab was well tolerated and had similar clinical benefit to other second-line chemotherapy regimens. The median treatment duration was 10.1 weeks, median progression-free survival was 3.2 months and median overall survival was 9.5 months. Learn more in Clinical Cancer Research.

Studies clarify impact of specific mutations on p53 tumor suppression
The most frequently mutated gene in all of cancer is TP53, which encodes the p53 tumor suppressor — a protein activated in response to cell damage. p53 plays a critical role in determining if damage can be repaired or if the cell should be eliminated. Loss or mutation of TP53 leads to uncontrolled cell growth and tumor development. Similarly, alterations in genes that regulate p53, such as MDM2, can inhibit the activity of p53 and allow cancer development. However, the impact of specific mutations in TP53 or MDM2 are not always clear. New studies from the laboratory of Gigi Lozano, Ph.D., shed light on how several distinct mutations alter the function of p53 and MDM2 proteins.

Researchers led by Shunbin Xiong, Ph.D., demonstrated that three different mutations in the DNA-binding domain of the p53 protein had similar effects on inhibiting normal p53 activity, but differed in their ability to promote osteosarcoma tumor development and metastasis. The different mutations activated different pathways and suggest unique therapeutic targets for each mutation. Learn more in Cancer Research.

A team led by Vinod Pant, Ph.D., demonstrated that alterations to one end of the MDM2 protein, known as the C-terminal end, affected the protein’s ability to regulate p53. MDM2 normally acts to inhibit p53 activity, serving to balance the function of the tumor suppressor. Using CRISPR gene editing in laboratory models, the researchers showed that altering the C-terminal end by even a single amino acid led to dramatic changes in p53 regulation. The findings confirm the role of this region of MDM2 in controlling p53 activity and provide insight into the mechanisms of this interaction. Learn more in Cancer Research.

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