MD Anderson Research Highlights for August 25, 2021

Newswise — 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. Current advances include clinical studies to investigate novel treatment strategies, a new understanding of cancer precursor lesions, identifying a calcium signaling receptor, characterizing nodal immune flair after immunotherapy, a community screening tool for BRCA testing and a new method for diagnosing Clostridioides difficile infections.

Combining venetoclax with intensive chemotherapy to treat younger patients with AML 

Previous research suggests that a combination of lower-intensity therapy and venetoclax, a drug that inhibits BCL2, improves survival in older patients with acute myeloid leukemia (AML). Tapan Kadia, M.D., and colleagues led the first trial evaluating intensive chemotherapy and venetoclax in younger, fitter patients. Venetoclax combined with cladribine, high-dose cytarabine and idarubicin (CLIA) was safe and effective against newly diagnosed AML or high-risk myelodysplastic syndrome in patients younger than 65. Out of 50 patients, 47 (94%) experienced a composite complete response and 37 (82%) had undetectable measurable residual disease (MRD). The overall survival rate after one year was 85%. Some patients experienced adverse events like febrile neutropenia and infections, but no deaths were deemed treatment-related. Overall, the trial suggests that venetoclax combined with CLIA results in high rates of durable, MRD-negative remissions and improves patient survival. Learn more in  The Lancet Haematology.

Single-cell evaluation distinguishes aggressive and benign DCIS lesions 

Ductal carcinoma in situ (DCIS) is a non-invasive lesion thought to be a precursor to invasive breast cancer. Unfortunately, it is currently unknown which lesions will progress to cancer and which will remain benign. Vidya C. Sinha, Ph.D., and Helen Piwnica-Worms, Ph.D., led a team to study indolent (slow-growing) and aggressive lesions in a breast cancer model system. Indolent and aggressive lesions had distinct gene expression profiles and contained a unique population of cell types. However, the lesions were indistinguishable once removed from their local environment, suggesting a role for external factors. Indeed, the lesions displayed distinct differences in immune cell compositions, with aggressive lesions surrounded by more suppressive immune cells. The suppressive immune signal IL-17 appeared important in aggressive lesion progression. These findings provide significant insights into features distinguishing DCIS lesions. Learn more in Nature Communications. 

Sequencing study clarifies the early development of gallbladder cancers 

Biliary tract intraepithelial neoplasia (BilIN) are benign tumors of the biliary tract — the organs responsible for producing and storing bile — that are thought to contribute to the development of gallbladder cancers. Understanding the connection between BilIN and gallbladder cancer could improve early detection and intervention efforts. Han Liang, Ph.D., and colleagues performed deep sequencing analysis of normal gallbladder tissue, tumor samples and BilIN isolated from the same patients. They discovered that some gallbladder cancers do arise from BilIN, but others follow an independent path. Aging was the major driver of mutations in all samples, and mutations in the CTNNB1 gene appear to be critical for cancer development. Further, genetic alterations called loss of heterozygosity (LOH) appear important in influencing future cancer development, suggesting that patients with high levels of LOH should be considered for earlier interventions. Learn more in Nature Communications. 

Lsm12 is a newly discovered receptor that regulates calcium signaling  

Signaling through calcium ions (Ca²⁺) is important for governing almost all cellular functions and physiological processes. Calcium ions are stored in cellular bodies, or organelles, that are triggered for release by molecules known as second messengers. NAADP (nicotinic acid adenine dinucleotide phosphate) is a second messenger responsible for triggering Ca²⁺ release from endolysosomes – a type of organelle – although the mechanism is not well understood. Research by Jiyuan Zhang, Ph.D., Xin Guan, Ph.D., Kunal Shah, Ph.D., and Jiusheng Yan, Ph.D., provided the first identification of an NAADP receptor responsible for triggering Ca²⁺ release. They demonstrated that the protein Lsm12 is part of a complex of endolysosomes that recognizes NAADP and stimulates ion release through specialized pores. This discovery provides clarity into the NAADP signaling pathway, which has been implicated in many maladies, including diabetes, autism and cardiovascular disease. Learn more in Nature Communications. 

Neoadjuvant immunotherapy can produce nodal immune flair in lung cancer 

Neoadjuvant immune checkpoint inhibitors (ICI) have shown clinical benefit for resectable non-small cell lung cancer (NSCLC). While imaging is the standard approach for evaluating the disease involvement of lymph nodes in patients, the impact of neoadjuvant immunotherapy on lymph nodes has not been extensively studied. Tina Cascone, M.D., Ph.D., and Boris Sepesi, M.D., analyzed nodal immune flare (NIF), a phenomenon in which the lymph nodes of patients treated with neoadjuvant ICI in the phase II NEOSTAR trial appear radiologically abnormal, but upon pathological evaluation are devoid of cancer. The investigators demonstrated that de novo non-caseating granulomas are a pathological hallmark of NIF. NIF occurred in seven out of 44 (16%) patients treated with neoadjuvant ICI but was not found in any of the 28 patients treated with neoadjuvant chemotherapy in an independent cohort. Although NIF can mimic disease progression on imaging, the tumor remains stable or shrinks. The nodes do not contain cancer but a sarcoid-like reaction that was absent prior to therapy. This study highlights the need for pathological examination to distinguish NIF from true disease progression to ensure appropriate clinical treatment planning. Learn more in Nature Communications.  

First-in-human study assesses safety of an investigational immunotherapy 

The glucocorticoid-induced tumor necrosis factor receptor (GITR), which modulates the adaptive and innate immune responses, offers a potential new target to improve immunotherapy. In preclinical studies, the GITR agonist GWN323 produced antitumor effects when combined with checkpoint inhibitors. Researchers hypothesized that a combination of the two compounds would produce a synergistic effect to improve antitumor efficacy. In a first-in-human, Phase I/Ib, open-label study, Sarina A. Piha-Paul, M.D., demonstrated that GWN323 was well-tolerated as a single agent and in combination with spartalizumab, a PD-1 checkpoint inhibitor, in adult patients with relapsed or refractory solid tumors and lymphomas. However, the study showed minimal antitumor activity as a single agent and modest clinical benefit as a combination therapy. These findings are important to add to the collective knowledge of GITR agonists and to better guide future clinical research. Learn more in the Journal for ImmunoTherapy of Cancer. 

Targeting the PAM pathway to treat solid tumors 

The PI3K/AKT/mTOR (PAM) pathway is a major intracellular signaling pathway that regulates cellular growth, proliferation and metabolism. Its activation has been identified as a frequently altered pathway in up to 30% of solid tumors, such as ovarian, breast and prostate cancers. The PAM pathway plays a critical role in therapeutic resistance and has emerged as a target for treating advanced refractory cancers. In a multi-institutional Phase I study led by Apostolia-Maria Tsimberidou, M.D., Ph.D., researchers tested the safety and efficacy of M2698, an oral p70S6K/AKT dual inhibitor, as monotherapy in patients with advanced solid tumors who failed standard therapies, or combined with trastuzumab and/or tamoxifen in patients with advanced, metastatic breast cancer. M2698 was well-tolerated as monotherapy and showed early signs of antitumor activity in patients with advanced refractory breast cancer when combined with trastuzumab or tamoxifen. Learn more in Journal of Hematology & Oncology.

CD63 regulates export of VEGF protein to resist anti-VEGF therapies 

Anti-VEGF therapies, which block the formation of new blood vessels by a tumor, are effective in treating many solid tumors. However, many cancers eventually develop resistance, and understanding how this occurs is important for predicting responses and developing new treatments. Researchers led by Shaolin Ma, M.D., Ph.D., and Anil K. Sood, M.D., demonstrated that cancer cells export the VEGF protein by releasing small membrane-bound packages, called extracellular vesicles. In response to anti-VEGF therapies, increasing quantities of VEGF protein are packed into vesicles, where they cannot be targeted by the drug. The exported VEGF is able to stimulate blood vessel formation in nearby cells, thus enabling tumor growth despite anti-VEGF therapies. The researchers discovered that packaging VEGF relied upon the action of the CD63 protein, perhaps offering a new target to block therapeutic resistance. Learn more in Cell Reports. 

Survey identifies women who are eligible for genetic counseling and testing  Women with a BRCA mutation have an increased lifetime risk of breast and ovarian cancer. Despite these risks and guidelines recommending risk reduction interventions, less than half of individuals who meet the criteria for BRCA1/2 genetic testing receive a referral for genetic counseling and testing. A team led by Banu Arun, M.D., developed a questionnaire that was provided to 34,851 patients undergoing mammography at a community breast imaging center. The study showed the feasibility of large-scale screening in identifying women eligible for genetic referral and testing. The study identified women with BRCA mutations and women who otherwise had a high lifetime risk of breast cancer, allowing providers to share improved risk-management strategies, such as breast MRI and chemoprevention, in addition to a standard mammogram. Learn more in Cancer. 

A potential new method to diagnose Clostridioides difficile infection 

A team led by Teny John, M.D., recently published a proof-of-concept study offering a new method to diagnose Clostridioides difficile infection (CDI). This infectious inflammation of the colon is associated with antibiotic treatment and can cause potentially life-threatening diarrhea. Diagnosing CDI is a complex and timely process that involves stool-based enzyme immunoassay and real-time polymerase chain reaction tests, which cannot distinguish infection from colonization. In this study, volatile organic compounds (VOCs) were analyzed in various clinical samples using selected ion flow tube mass spectrometry. The authors show that breath VOC analysis was able to distinguish patients with CDI from those without, with an accuracy of 93%, while stool and plasma VOC analysis could distinguish them with accuracies of 86% and 91%, respectively. These findings support further research to validate this rapid, sensitive and specific point-of-care testing method for early diagnosis of CDI. Learn more in PLOS ONE.   

In case you missed it

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

• CPRIT awards nearly $13 million in support of MD Anderson research

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