MD Anderson Research Highlights for June 1, 2022

Featuring new biomarkers for CAR T responses and toxicities, novel treatment targets for a variety of cancers, and clinical data for AML and cancers of unknown primary

The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into recent basic, translational and clinical cancer research from MD Anderson experts. Current advances include new biomarkers to predict chimeric antigen receptor (CAR) T cell therapy outcomes and neurotoxicities, novel treatment targets for pre-cancerous pancreatic lesions and T-cell acute lymphoblastic leukemia, a new approach to improve immunotherapy responses in cold tumors, a profile of synthetic lethal targets for cancers with tumor suppressor loss, and promising clinical data for acute myeloid leukemia and cancers of unknown primary.

Pre-treatment DNA copy-number changes predict CAR T cell therapy outcomes
Chimeric antigen receptor (CAR) T cell therapy targeting CD19 can achieve long-term remissions in many patients with advanced large B-cell lymphoma, but more than half will not benefit from this approach. Predictive biomarkers are needed to identify those not likely to respond so that physicians can consider additional or alternative treatments. In a new study led by Hua-Jay (Jeff) Cherng, M.D., Michael Green, Ph.D., and Jason Westin, M.D., researchers discovered that genetic copy-number alterations (CNAs) evident in pre-treatment blood samples were predictive of inferior response rates to CD19 CAR T cell therapy. The team performed low-pass whole genome sequencing on cell-free DNA isolated from the blood of 122 patients before treatment. A high CNA score, denoting genomic instability, was associated with significantly lower complete response rates, progression-free survival and overall survival when compared to patients with a low CNA score. By combining this score with traditional markers of tumor bulk, the researchers built a risk model to reliably predict patient outcomes. Learn more in Blood.

PPARδ signaling accelerates cancer progression in KRAS-mutant pancreatic lesions
Pancreatic intraepithelial neoplasia (PanIN) are lesions within the pancreas that can develop into pancreatic cancer. Most PanIN lesions have mutations in the KRAS gene that can drive cancer development, but relatively few lesions actually progress to cancer. Understanding factors that promote progression is critical to developing intervention strategies. Researchers led by Yi Liu, Ph.D., Xiangsheng Zuo, M.D., Ph.D., and Imad Shureiqi, M.D., discovered that activated PPARδ — a hormone receptor found in the cell nucleus — accelerates progression of KRAS-mutant PanIN lesions. The researchers demonstrated that PPARδ expression is elevated in PanIN lesions through the activity of mutant KRAS. When activated by a synthetic ligand called cardarine (GW501516) or a high-fat diet, PPARδ stimulates pancreatic epithelial cells to secrete the CCL2 chemokine, which recruits suppressive immune cells into the tumor microenvironment. Blocking signaling downstream of CCL2 suppressed pancreatic cancer development driven by PPARδ. The findings suggest that targeting the PPARδ pathway may be a viable strategy to prevent PanINs from progressing to pancreatic cancer. Learn more in Nature Communications.

Targeting oxidative phosphorylation may be effective in NOTCH1-mutant T-ALL
T-cell acute lymphoblastic leukemia (T-ALL) is an aggressive leukemia often driven by NOTCH1 mutations. Unfortunately, targeting NOTCH1 has proven challenging, so alternative therapeutic approaches for these cancers are needed. Researchers led by Natalia Baran, M.D., Ph.D., and Marina Konopleva, M.D., Ph.D., demonstrated that the oxidative phosphorylation (OxPhos) metabolic pathway is critical for survival and chemotherapy resistance in NOTCH1-mutant leukemia cells. Mutant NOTCH1 led to activation of the OxPhos pathway, and targeting OxPhos with IACS-10759 — a small-molecule inhibitor developed by MD Anderson’s Therapeutics Discovery division — blocked proliferation in NOTCH1-mutant cells. Blocking OxPhos led to metabolic reprogramming that increased dependency on glutamine metabolism. Combining IACS-10759 with the chemotherapy asparaginase or with glutaminase inhibitors, both of which disrupt glutamine metabolism, leveraged this vulnerability and led to profound tumor reductions in preclinical T-ALL models. The findings suggest this strategy warrants further study as a new treatment approach. Learn more in Nature Communications.

Preclinical study turns “cold” tumors “hot” through LFA-1 activation
Immune checkpoint blockade targeting PD-1 and CTLA-4 has transformed cancer treatment, particularly in melanoma, but not all patients benefit from immunotherapy. Multiple studies have identified a “cold” tumor microenvironment (TME), with few T cells, as one reason immunotherapy is not successful against some cancers. Lymphocyte function–associated antigen-1 (LFA-1) is known to recruit T cells to the TME. A preclinical study led by Yared Hailemichael, Ph.D., used 7HP349, a small molecule activator of LFA-1, alone and in combination with anti-CTLA-4 therapy in a non-T cell inflamed tumor model. While 7HP349 monotherapy had a modest effect, T cells were enriched in the TME when combining 7HP349 with anti-CTLA-4 therapy. This proof-of-concept study lays the groundwork for further research on LFA-1 activation to improve response to immune checkpoint blockade. Learn more in JCI.

Genomic screen finds potential treatment targets for cancers with tumor suppressor loss
Tumor suppressors normally work to block cancer growth, but when they are lost or inactivated by mutation, abnormal cells can grow unchecked. Unfortunately, this loss of function means that tumor suppressors cannot be targeted directly. One alternative strategy is to take advantage of synthetic lethality, in which cancer cells with tumor suppressor loss become hypersensitive to drugs targeting related pathways. To identify potential synthetic lethal targets, a research team led by Junjie Chen, Ph.D., and Traver Hart, Ph.D., performed a genome-wide screen in 12 engineered cell lines, each with a common tumor suppressor knocked out. Using CRISPR/Cas9 gene editing, the researchers systematically inactivated more than 18,000 genes in each cell line and identified more than 300 genes that may be potential synthetic lethal targets for at least one tumor suppressor. Interestingly, they discovered that targeting one tumor suppressor may be a viable therapeutic strategy for cancers with loss of another tumor suppressor. This study provides a useful resource for researchers to identify novel therapeutic strategies for cancers with tumor suppressor loss. Learn more in Science Advances.

New study offers potential treatment for cancer of unknown primary
Cancer of unknown primary (CUP) is an aggressive rare disease in which the cancer has metastasized to other parts of the body, but the origin of cancer growth cannot be determined. Because the primary site is unknown, this type of cancer is difficult to treat with limited therapeutic options. In a Phase II basket trial for independent rare tumor cohorts, including CUP, Aung Naing, M.D., and a team of MD Anderson researchers evaluated the safety and efficacy of pembrolizumab in 29 patients with advanced CUP. Of the 25 evaluable patients, seven (28%) achieved non-progression at 27 weeks. In addition, the drug achieved an overall response rate of 20%, with immune-related partial response in five patients and a median duration of response of 14.7 months. Treatment-related adverse events of any kind were observed in 19 patients (76%) and grade ≥3 in four patients (16%), respectively. One patient had grade 3 immune-related acute kidney injury requiring treatment discontinuation. Overall, pembrolizumab was well-tolerated and demonstrated encouraging efficacy in patients with CUP. Learn more in the Journal for ImmunoTherapy of Cancer.

Combination induction therapy for AML shows favorable responses and durable survival
Most younger patients with acute myeloid leukemia (AML) respond favorably to initial chemotherapy, but many will experience a subsequent relapse. Once disease relapse occurs, outcomes are poor and new therapies are needed. An expanded study, led by Courtney DiNardo, M.D., Hagop Kantarjian, M.D., and Curtis Lachowiez, M.D., found that an intensive regimen of fludarabine, cytarabine, granulocyte colony-stimulating factor and idarubicin (FLAG-IDA) combined with venetoclax produced deep remissions that correlated with durable survival. The overall response rate was 98% and minimal residual disease (MRD)-negative complete response rates exceeded 90%. Median event-free survival (EFS) and overall survival (OS) were not reached but were estimated at 24 months to be 64% and 76%, respectively. In patients attaining MRD-negative responses, estimated EFS and OS were 75% and 82%. The combination therapy helped bridge patients to successful stem cell transplants. The study continues to enroll patients with newly diagnosed and relapsed or refractory AML at MD Anderson. Learn more in the American Journal of Hematology.

Clonal hematopoiesis linked to severe neurotoxicity following CAR T cell therapy
Durable responses are achieved in many patients with hematologic cancers treated with chimeric antigen receptor (CAR) T cell therapy, but the treatments can cause significant neurological toxicities. Despite progress, many of the underlying causes of these toxicities remain unknown. Clonal hematopoiesis (CH) — the expansion of hematopoietic stem cells with somatic mutations — can drive systemic inflammation, but its connection to these neurotoxicities was not understood. In a new study, Neeraj Saini, M.D., Sattva Neelapu, M.D., and Koichi Takahashi, M.D., Ph.D., and colleagues discovered that CH mutations, particularly those with epigenetic machineries, are linked with severe-grade neurotoxicities in lymphoma patients treated with CD19 CAR T cell therapy. Through targeted DNA sequencing, they detected CH mutations in 36.8% of pre-treatment samples from 114 patients. Grade 3 or higher neurotoxicities were observed in 45.2% of patients with CH, compared to just 25% of those without CH. Future studies will aim to understand how CH may drive neurotoxicity and to develop novel intervention strategies to prevent or treat these conditions. Learn more in Blood Cancer Discovery.

In case you missed it
Read below to catch up on recent MD Anderson press releases.

KRAS-mutant pancreatic lesion with PPARδ overexpression following a high-fat diet. Epithelial duct-like tumor cells are shown in red, fibroblast cells in green, and cell nuclei in blue. Image courtesy Xiangsheng Zuo, M.D., Ph.D.