MD Anderson Research Highlights for August 11, 2021

HOUSTON ― 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 insights into anti-tumor responses, a targeted therapy combination for biliary tract cancers, biomarkers that may predict response to DNA damage repair inhibitors, a “virtual biopsy” using artificial intelligence to characterize tumors, new targeted and immunotherapy approaches for pancreatic cancer, understanding the impact of TP53 mutations on acute myeloid leukemia treatments, as well as a new strategy to overcome treatment-resistant KRAS-mutant lung cancer.

CXCR6 is essential for T cell-mediated tumor control

Cytotoxic T lymphocytes (CTLs) are T cells responsible for recognizing and eliminating cancer cells. To maintain a successful anti-tumor response, CTLs must receive appropriate signals to promote their survival and overcome a suppressive environment. Mauro Di Pilato, Ph.D., led research to identify the CXCR6 signaling receptor as a critical factor for CTL survival in the tumor microenvironment. The researchers demonstrated that CTLs congregate near blood vessels in tumors, where dendritic cells produce a variety of pro-survival factors. The dendritic cells produce CXCL16, the ligand for CXCR6, to guide CTLs into these niches where they can proliferate and sustain the anti-tumor response. CXCR6 expression was predictive of positive outcomes in patients, suggesting that this discovery may improve future immunotherapy approaches. Learn more in Cell.

Pertuzumab plus trastuzumab shows promise for biliary tract cancers in MyPathway study

Biliary tract cancers are a rare group of gastrointestinal cancers with limited treatment options and median overall survival of less than one year. The MyPathway study is a basket clinical trial enrolling patients with a variety of HER2-positive advanced solid tumors. Results from the phase II study of trastuzumab and pertuzumab for biliary tract cancers were reported recently by Milind Javle, M.D., and colleagues. The cohort enrolled 39 patients with metastatic, previously-treated biliary tract cancers with HER2 amplification, overexpression or both. Patients received a dual regimen of anti-HER2 targeted therapies, pertuzumab plus trastuzumab. Partial response was achieved in nine patients (23%) and disease control in 20 patients (51%). Responses were durable for a median of 10.8 months in those with objective response. Grade 3-4 treatment-emergent adverse events were observed in 18 patients (46%), while only three patients (8%) had treatment-related adverse events. Learn more in The Lancet Oncology.

Identifying biomarkers to predict response to DNA damage repair inhibitors

Genomic instability is a hallmark of cancer cells. Targeted therapies against DNA damage repair (DDR) proteins, such as ATM, ATR, CHK1 and DNAPK, have emerged as effective treatments, but there is a lack of biomarkers to predict the patients most likely to benefit. Researchers led by Chao Wang, Ph.D., Mengfan Tang, Ph.D., Zhen Chen, Ph.D. and Junjie Chen, Ph.D., conducted a whole-genome CRISPR/Cas9 screen to identify vulnerabilities that affect responses to DDR inhibitors. They discovered that genetic loss of YWHAE sensitized cells to CHK1 inhibitors and APEX1 loss made cells vulnerable to DNAPK inhibition, whereas KLHL15 loss protected cells from ATM inhibitors. Additionally, combining PARP inhibitors with certain DDR inhibitors was very effective at inducing cancer cell deaths. The findings suggest that these genetic vulnerabilities may one day help to guide treatment selection for patients. Learn more in Nucleic Acids Research.

Researchers develop new radiological tumor classification across imaging modalities and histologies using artificial intelligence

Radiological imaging allows doctors to screen, diagnose, stage and evaluate treatment response and surveillance. However, it also can provide critical information about tumor phenotypes by using high-throughput extraction of quantitative image features from radiological scans to predict therapy response and outcomes. In an international, multi-institutional study of 1,682 patients, Jia Wu, Ph.D., developed a “virtual biopsy” using a radiological tumor classification system to characterize tumor morphology and spatial heterogeneity with deep learning artificial intelligence. By analyzing pre-treatment MRI and CT scans for three cancer types (non-small cell lung cancer, breast cancer and glioblastoma multiforme) to define quantitative features, he and his team identified and validated four radiographic subtypes to automate tumor segmentation. This automation will help improve prognosis and response to different cancer treatments, including surgery, radiation and chemotherapy, as well as immunotherapy. As a result, the use of deep learning tumor classification may be applied in precision medicine in the future. Learn more in Nature Machine Intelligence.

Discovery of a new genetic vulnerability in pancreatic cancer

Recent studies demonstrated that abnormal epigenetic regulation – chemical modifications that control chromatin structure and gene expression – contributes to pancreatic cancer development. To identify epigenetic vulnerabilities that may be targeted with new therapies, researchers led by Virginia Giuliani, Ph.D., and Timothy Heffernan, Ph.D., used an innovative in vivo screening approach on patient-derived pancreatic cancer models. They identified protein arginine methyltransferase 1 (PRMT1) as an epigenetic factor critical for pancreatic cancer survival. They found that PRMT1 is a master regulator of RNA metabolism required for DNA damage repair, DNA replication and genomic stability. Inhibiting PRMT1 resulted in a cascade of events that impaired tumor growth, suggesting this may be a novel treatment strategy. MD Anderson’s Therapeutics Discovery division currently is developing a novel PRMT1 inhibitor for future clinical studies. Learn more in Nature Communications.

Discovering a new DNA repair protein points to novel predictive biomarker

DNA double-strand breaks (DSBs) – a toxic form of damage in which both strands of the DNA helix are broken – can be generated through ionizing radiation. Repairing DSBs requires a coordinated process with multiple repair proteins, including MRE11. New research led by Zu Ye, Ph.D., John Tainer, Ph.D., and Zamal Ahmed, Ph.D., discovered an important new role for the protein GRB2 in binding to MRE11 and supporting proper DSB repair. This study is the first to identify this new function of GRB2, previously known as a signaling protein within the Ras/MAPK pathway. The researchers clarified the molecular mechanism by which GRB2 interacts with MRE11 and demonstrated that loss of GRB2 sensitized cells to PARP inhibitors, which target other DSB repair proteins. The findings suggest that GRB2 may be useful as a predictive biomarker for patients receiving PARP inhibitors or radiation therapy. Learn more in Science Advances.

Stimulating immune reprogramming to improve immunotherapy responses in pancreatic cancer

Immune checkpoint inhibitors can help T cells overcome functional brakes and eliminate cancer cells in many tumor types. However, pancreatic cancers have immune-suppressive tumor microenvironments (TMEs), and checkpoint inhibitors alone are not effective. Researchers led by Casey Ager, Ph.D., and Michael A. Curran, Ph.D., hypothesized that hyper-activation of the STING immune signaling pathway, which is critical to host defense against infections, may override the suppressive TME imposed by pancreatic cancers and sensitize the tumors to checkpoint inhibitors. Intratumoral injection of a potent STING activator, co-developed with MD Anderson’s Therapeutics Discovery division, resulted in tumor regression when combined with checkpoint inhibitors in animal models. The researchers detailed the molecular pathways responsible for this immune reprogramming and demonstrated a similar response in human cells. Learn more in the Journal for ImmunoTherapy of Cancer.

TP53 mutations developed during AML treatment can impact therapeutic strategies

Patients with acute myeloid leukemia (AML) who carry a TP53 mutation, which is a genetic mutation in the body’s DNA repair regulator, tend not to respond to standard treatments and experience poorer outcomes relative to those without the mutation. In a retrospective analysis of 200 patients with AML without the TP53 mutation and who relapsed or did not respond to frontline therapy, researchers led by Nicholas Short, M.D., found that 15% of patients developed a newly detectable TP53 mutation at some point over the course of therapy. Further, these mutations were more common after more intense therapies and after stem cell transplant. These findings suggest that TP53 mutations may occur throughout the course of AML treatment, and monitoring these changes may be beneficial as new therapies are developed to treat AML by targeting TP53 mutations. Learn more in the American Journal of Hematology.

Targeting CDK4 to overcome resistance in KRAS-mutant lung cancer

Although KRAS was identified as an oncogenic driver in non-small cell lung cancer (NSCLC) over 30 years ago, no approved therapy had successfully targeted the mutant protein until this year. Targeting the mutation, which is found in about 30% of NSCLC tumors, is difficult because KRAS-mutant NSCLC tends to be heterogeneous and resistant to treatment. Research has shown that epithelial-to-mesenchymal transition (EMT) contributes to these challenges and, ultimately, poor patient outcomes. New research, led by Don Gibbons, M.D., Ph.D., used functional shRNA screens plus in vitro and in vivo models to confirm that mesenchymal tumor cells depend on CDK4 for survival and to demonstrate how CDK4 inhibitors could be used to overcome EMT-mediated therapeutic resistance. These findings lay the groundwork for testing new treatment combinations in KRAS-mutant lung cancer. Learn more in JCI Insight. 

In case you missed it

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

• Researchers discover new factor in preventing phenylketonuria, offering new treatment strategy
• Statins may improve survival for triple-negative breast cancer patients

– 30 –