MD Anderson Research Highlights for October 6, 2021

Featuring discoveries in novel targeted therapies, tools to predict immunotherapy responses and insights pointing to new treatment targets

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 promising clinical results for therapies targeting HER2, FGFR and TGF- β, discovering new drivers of lung cancer development, novel approaches to predict immune responses and overcome immunotherapy resistance, and a novel combination therapy for prostate cancer.

Poziotinib shows antitumor activity in advanced HER2 exon 20 mutant lung cancer

Patients with HER2 exon 20 mutant non-small cell lung cancer (NSCLC) currently do not have an FDA-approved targeted therapy option. This single-arm Phase II study assessed the safety and efficacy of the irreversible covalent tyrosine kinase inhibitor poziotinib in 30 patients with advanced HER2 exon 20 mutant NSCLC, 90% of whom received prior platinum-based chemotherapy. Yasir Elamin, M.D.John Heymach, M.D., Ph.D., and colleagues reported a confirmed objective response rate of 27%. The median progression-free survival was 5.5 months, and median overall survival was 15 months. Skin rash, diarrhea and nail inflammation were the most comment treatment-related adverse events. There was one possible treatment-related death due to grade 5 pneumonitis. The FDA granted fast track designation to poziotinib in March. Learn more in the Journal of Clinical Oncology.

New study targets FGFR aberrations to treat patients with advanced solid tumors

Fibroblast growth factor receptors (FGFRs) are a family of cell signaling proteins involved in various functions and processes, but deregulation of FGFR signaling through genetic aberrations can drive cancer development. These aberrations vary in frequency, oncogenic potential and sensitivity to therapies, making the pathway difficult to target. Most FGFR inhibitors being evaluated are focused on reversible ATP-competitive inhibitors that have shown activity in specific FGFR aberrations and have been limited by the development of resistance. In a Phase I dose-expansion study, Funda Meric-Bernstam, M.D., and colleagues investigated the clinical activity and tolerability of futibatinib — a highly selective, irreversible FGFR1-4 inhibitor — as a disease-agnostic option for patients with advanced solid tumors bearing a variety of FGFR alterations, including mutations, amplifications and fusions/rearrangements. The trial included heavily pretreated patients with many cancer types, including cholangiocarcinoma and gastric, urothelial, central nervous system, head and neck, and breast cancer. The researchers demonstrated encouraging antitumor activity across cancers with a manageable safety profile, and they identified novel genomic alterations as potential FGFR inhibitor targets for future exploration. Learn more in Cancer Discovery.

NSD2 epigenetic regulation cooperates with mutant KRAS to promote lung cancer

The protein NSD2 plays an important role in regulating epigenetic modifications to histone proteins, which in turn affect chromatin structures and gene expression. Abnormal NSD2 activity has been linked to several hematologic cancers, but its role in solid tumors is not well understood. Research co-led by Liyong Zeng, Ph.D., and Pawel Mazur, Ph.D., together with collaborators, demonstrated that NSD2 plays a key role in the development of lung cancer and may have potential as a therapeutic target. NSD2 expression was frequently elevated in lung cancer tissue, and higher expression correlated with worse outcomes. Activated NSD2 cooperated with mutant KRAS to accelerate tumor progression through its regulation of histones, whereas loss of NSD2 blocked tumor growth. Combining NSD2 depletion with a targeted therapy against MEK1/2, which acts downstream of mutant KRAS, resulted in nearly complete tumor regression. Learn more in Molecular Cell.

AI tool predicts mutant proteins likely to elicit an immune response

Genetic mutations lead to the production of mutant proteins, or neoantigens, which can be recognized as abnormal by the immune system. However, only a small percentage of neoantigens stimulate an immune response from T cells, and predicting those reactive neoantigens has been a challenge in the field. Alexandre Reuben, Ph.D., and colleagues developed an artificial intelligence technique called pMTnet to predict the binding specificity between neoantigens and T-cell receptors. The research team validated the accuracy of pMTnet and found it outperformed current tools. Using pMTnet and data from The Cancer Genome Atlas, they demonstrated that neoantigens are generally more reactive than other self-antigens. The tool also was able to predict which patients had better responses to immunotherapy and better outcomes. Going forward, this tool may be useful to guide treatment approaches or to design better cancer vaccines or cell therapies. Learn more in Nature Machine Intelligence.

Loss of chromosome region 9p21 associated with resistance to immunotherapy

Immune checkpoint inhibitors have dramatically improved outcomes for many patients, but some cancers do not respond to current therapies. Understanding this resistance is critical to providing patients with the best treatment options and developing more effective therapies. Researchers led by Guangchun Han, Ph.D., Guoliang Yang, M.D., Jianjun Gao, M.D., Ph.D., and Linghua Wang, M.D., Ph.D., demonstrated that loss of the 9p21 chromosomal region, which occurs in 13% of all cancers, results in an immune-suppressive tumor microenvironment and resistance to checkpoint inhibitors. Tumors with 9p21 loss had fewer infiltrating immune cells, lower immune cell activation and lower activation of immune-suppressive signaling. Analysis of eight published trials revealed patients with 9p21 loss had significantly lower response rates to checkpoint inhibitors and worse outcomes. The researchers developed a model to predict patient responses based on 9p21 status, PD-L1 expression and tumor mutational burden. Learn more in Nature Communications.

First-in-human study targets TGF-β to treat patients with advanced cancer

Transforming growth factor-beta (TGF-β) plays critical roles in normal cellular functions, but it also can enhance tumor progression in advanced stages of cancer. In a multicenter Phase I study led by Timothy Yap, M.B.B.S., Ph.D., researchers showed that LY3200882, a next-generation TGF-β receptor type 1 inhibitor, was well tolerated and induced antitumor activity against advanced cancers — including glioblastoma, pancreatic cancer and head and neck squamous cell cancer. LY3200882 as both monotherapy and in combination with other antitumor agents also demonstrated robust pharmacokinetic and pharmacodynamic efficacy. LY3200882 alone showed early signs of antitumor activity in glioblastoma. When given in combination with gemcitabine and nab-paclitaxel, LY3200882 showed promising antitumor activity in treatment-naïve patients with advanced pancreatic cancer. These findings add to the growing clinical evidence supporting further studies on LY3200882 in combination with gemcitabine and nab-paclitaxel to address the urgent clinical need of providing more effective treatment options for patients with advanced pancreatic cancer. Learn more in Clinical Cancer Research.

Modeling predicts kinase inhibitors for late-stage prostate cancer 
Metastatic castration-resistant prostate cancer (CRPC), a form of advanced prostate cancer in which hormone therapy no longer stops cancer growth, is associated with poor patient outcomes. Eleonora Dondossola, Ph.D., and colleagues used computational modeling to predict which kinase inhibitors (KIs) would reduce the spread of CPRC. The team identified two compounds that suppressed CPRC cell growth in cell culture and in subcutaneous primary tumors, but therapy resistance emerged in bone metastases. Further analysis demonstrated that a combination of these KIs with standard-of-care chemotherapy overcomes resistance, enhancing both tumor response and survival. These results suggest that combining multi-targeted KIs with chemotherapy may represent an effective strategy for CRPC treatment. Learn more in the Proceedings of the National Academy of Sciences.

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This image shows how lung cancer cells invade surrounding tissues and start to spread (metastasis). Source: National Cancer Institute