MD Anderson Research Highlights for December 6, 2021

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. Clinical advances include positive data with targeted therapies for HER2 exon 20 mutant lung cancer, for older patients with mantle cell lymphoma and for BRAFV600E-mutant gliomas. Additional discoveries include insights into chromosomal instability and immunotherapy resistance in pancreatic cancer, the genomic landscape of small-cell lung cancer, hematopoietic stem cell decline with telomere shortening, identifying tumor suppressors in CRISPR screens, and physiological responses to fasting.

Multi-center study demonstrates clinical benefit for poziotinib in HER2 exon 20 mutant lung cancer

There is currently an unmet need for targeted therapies to treat the 2% to 5% of non-small cell lung cancers (NSCLC) with HER2 exon 20 oncogenic driver mutations. Cohort 2 of the Phase II ZENITH20 clinical trial assessed the small molecule inhibitor poziotinib in 90 patients with previously treated HER2 exon 20 mutant NSCLC. Xiuning Le, M.D., Ph.D., John Heymach, M.D., Ph.D., and colleagues reported an objective response rate of 27.8% after a median follow-up of nine months. Most patients (74%) saw their tumors shrink. The disease control rate was 70%, median progression-free survival was 5.5 months and median duration of response was 5.1 months. Thirteen percent of patients permanently discontinued treatment due to adverse events. The results echo the findings from a smaller, single-institution study previously published by MD Anderson researchers. Based on the results of this smaller study, the FDA granted fast-track designation to poziotinib in March 2021. Learn more in the Journal of Clinical Oncology.

Utilizing ibrutinib and rituximab combination as first-line “chemotherapy-free” treatment of older patients with mantle cell lymphoma

Patients with mantle cell lymphoma (MCL) are generally treated with systemic chemotherapy, although older patients tend to have poorer tolerance, quality of life and outcomes with chemotherapy. Since most MCL patients are older, alternative treatments are needed. A research study led by Preetesh Jain, M.D. Ph.D., and Michael Wang, M.D., investigated the safety and efficacy of a chemotherapy-free combination of ibrutinib and rituximab administered to 50 previously untreated older (≥ 65 years) patients with MCL. This single-institution single-arm Phase II trial treated patients with the combination for two years, then continued ibrutinib therapy alone. The overall response rate was 96%, and 71% of trial enrollees experienced a complete response. While 22% of patients experienced atrial fibrillation, the combination was found to be safe and no on-study deaths were noted. The combination of ibrutinib and rituximab is promising for MCL treatment, and the researchers suggest conducting a randomized trial to definitively prove its effectiveness. Learn more in the Journal of Clinical Oncology.

New combination therapy offers promising treatment for BRAFV600E-mutant gliomas

Standard treatments for gliomas — the most common primary brain tumors — consist of a combination of surgery, radiation and temozolomide-based or lomustine-based chemotherapy. However, because current options have been associated with poor response rates and prognoses, especially for patients with the BRAFV600E mutations, finding an effective treatment to improve outcomes remains an unmet clinical need. A team of researchers led by Vivek Subbiah, M.D., conducted the Phase II Rare Oncology Agnostic Research (ROAR) basket trial to assess the activity and safety of dabrafenib plus trametinib combination treatment in patients with BRAFV600E-mutated high-grade glioma (HGG) and low-grade glioma (LGG), as well as other rare cancers. In the glioma cohorts, the combination therapy demonstrated clinically meaningful activity — a 33% and 69% objective response rate in HGG and LGG, respectively — and was well tolerated, with a safety profile consistent with that in other indications. These findings suggest that BRAFV600E testing could potentially be adopted in clinical practice for patients with glioma. Learn more in The Lancet Oncology.

Glucocorticoid receptor in pancreatic cancer cells promotes immunotherapy resistance

Immune checkpoint inhibitors have not been effective in treating patients with pancreatic cancer, in part due to an immune-suppressive tumor microenvironment. Glucocorticoid signaling is thought to suppress immune cell activity, but new research led by Yalan Deng, Ph.D., and Li Ma, Ph.D., discovered an important role for the glucocorticoid receptor (GR) within pancreatic cancer cells. They demonstrated GR signaling in pancreatic cancer cell lines regulates expression of the immune checkpoint protein PD-L1 and the antigen presentation protein MHC-I. In preclinical models, either genetic depletion or therapeutic inhibition of GR lowered PD-L1 and elevated MHC-I levels, sensitizing otherwise immunotherapy-resistant pancreatic tumors to checkpoint inhibitors. High GR expression in pancreatic cancer patient samples correlated with high PD-L1 expression, low MHC-I expression and poorer clinical outcomes. The findings suggest that GR signaling plays an important role in cancer cells to suppress the anti-tumor immune response, pointing to a potential new therapeutic target. Learn more in Nature Communications.

Study provides new insights on genomic landscape of small-cell lung cancer

Small-cell lung cancer (SCLC) is an aggressive form of lung cancer with high rates of recurrence and early metastasis. Research has suggested that complex genomic intratumor heterogeneity contributes to treatment resistance. In this study, researchers applied whole-exome sequencing and T cell receptor sequencing to 50 samples from 19 limited-stage SCLC tumors to investigate the immunogenomic landscape and assess impact on patient survival. Jianjun Zhang, M.D., Ph.D., Lauren Averett Byers, M.D., and Alexandre Reuben, Ph.D., reported finding a homogeneous mutational landscape overall, but an extremely cold and heterogeneous T cell receptor repertoire, which was associated with higher chromosomal copy number aberration burden and lower overall survival. Learn more in Nature Communications.

Understanding hematopoietic stem cell decline in response to telomere shortening

DNA damage is a major cause of stem cell decline, and one precursor to persistent DNA damage is telomere erosion. Telomeres naturally shorten over time, but erosion can be accelerated by mutations in telomere maintenance genes. It is unclear how shortened telomeres lead to stem cell decline, but hematopoietic stem cells (HSCs) are particularly vulnerable to telomere-maintenance defects. Researchers led by Natthakan Thongon, Ph.D., and Simona Colla, Ph.D., sought to understand how shortened telomeres affect HSCs and lead to bone marrow failure syndromes. Using single-cell analysis, they discovered that shortened telomeres activate the innate immune response in HSCs, driving persistent metabolic activation and differentiation processes that limit their self-renewal capacity and lead to cell exhaustion. These processes were overcome by targeting the Ifi20x/IFI16 family of DNA sensors with an oligodeoxynucleotide comprised of telomeric repeats, suggesting that targeting the IFI16 signaling axis may prevent HSCs’ functional decline in the face of telomere shortening. Learn more in Nature Communications.

Harnessing CRISPR genetic screens to identify new tumor suppressors

Genetic screens using CRISPR gene editing allow researchers to efficiently inactivate individual genes to determine effects on cancer cell survival. Most screens look for cell death to identify genes essential for growth, but screens also can point to tumor suppressor genes when knockouts cause increased proliferation. Using more than 1,000 published screens, researchers led by W. Frank Lenoir, Ph.D., and Traver Hart, Ph.D., demonstrated a novel approach to identify potential tumor suppressors. Through this technique, they identified a network of 145 suppressor genes across 22 functional groups. The researchers discovered and validated that components of the fatty acid metabolism act as tumor suppressors in a subset of acute myeloid leukemia (AML) cells, and expression of those genes was correlated with patient survival outcomes. The study provides not only a new technique for identifying tumor suppressors, but also points to a potential prognostic marker and therapeutic target for AML. Learn more in Nature Communications.

A new understanding of how fasting protects against therapy toxicity

Normal tissue toxicity is a major limitation in delivering effective doses of chemotherapy and radiation. Preclinical studies from the laboratory of Helen Piwnica-Worms, Ph.D., showed fasting can blunt the effects of high-dose chemotherapy and — in collaboration with the laboratory of Cullen Taniguchi, M.D., Ph.D. — radiation in part by protecting intestinal stem cells, but the mechanism remains unclear. A new study led by Christopher Terranova, Ph.D., Kristina Stemler, Ph.D., Kunal Rai, Ph.D., and Piwnica-Worms discovered that fasting leads to epigenetic modifications in small intestinal crypt cells that activate specific metabolic pathways. During fasting, the major metabolite produced by the body is β-hydroxybutyrate (β-OHB), which the researchers demonstrated can directly modify histone proteins to trigger the expression of metabolic genes in the small intestine. This mechanistic understanding may help researchers develop approaches to protect against side effects without needing to fast, possibly expanding the therapeutic window of chemotherapy and radiation. Learn more in Cell Reports.

In case you missed it

Read below to catch up on recent MD Anderson press releases across the spectrum of cancer research.

Infiltration of cytotoxic T cells (green) into a pancreatic tumor following combination treatment with glucocorticoid receptor antagonist and dual immune checkpoint inhibitors. Image courtesy Li Ma, Ph.D., laboratory.