MD Anderson Research Highlights: AACR 2023 Special Edition

HOUSTON ― The University of Texas MD Anderson Cancer Center’s Research Highlights showcases the latest breakthroughs in cancer care, research and prevention. These advances are made possible through seamless collaboration between MD Anderson’s world-leading clinicians and scientists, bringing discoveries from the lab to the clinic and back.

This special edition features presentations by MD Anderson researchers at the American Association for Cancer Research (AACR) Annual Meeting 2023. In addition to these studies, forthcoming press releases will feature groundbreaking research on perioperative immunotherapy for operable lung cancer (Abstract CT005), a novel allogeneic chimeric antigen receptor (CAR) T cell therapy for clear cell renal cell carcinoma (Abstract CT011), new targeted therapies for cancers with specific mutations (Abstracts CT006, CT016, CT018), genetic markers for response to KRAS G12C inhibitors in lung cancer (Abstract 3431), and new targets for immunotherapy resistance in brain metastases from renal cell carcinoma (Abstract 5788).

More information on all MD Anderson AACR Annual Meeting content can be found at MDAnderson.org/AACR.  

First-in-human Phase I trial examines “pan-IDH” targeted inhibitors in advanced AML (Abstract CT026)
IDH1 and IDH2 mutations are present in approximately 20% of patients with acute myeloid leukemia (AML). While there are approved small-molecule inhibitors targeting IDH1 and IDH2, relapses remain common. After preclinical research on the “pan-IDH” targeted inhibitor LY3410738 demonstrated potency in the setting of IDH secondary resistance mutations, researchers led by Courtney DiNardo, M.D., evaluated the use of LY3410738 in a first-in-human study including 130 patients from around the world. Treatment was well tolerated, with sustained 2-hydroxyglutarate inhibition in IDH1-mutated patients at all dose levels and in IDH2-mutated patients at higher dose levels. Preliminary efficacy was observed in both IDH1– and IDH2-mutant patients, with most responses occurring in those who had never received prior BCL2 inhibitor therapy and had not received prior IDH-targeted therapy. The Phase I trial is ongoing, with current activity focused on adding the treatment to standard frontline AML therapy. DiNardo will present trial results on April 16.  

First-in-class targeted therapy FHD-286 significantly reduces AML burden in laboratory models (Abstract 1140)
New preclinical research led by Kapil Bhalla, M.D., and Warren Fiskus, Ph.D., demonstrated treatment with FHD-286, which targets the BRG1/BRM proteins, induces differentiation followed by cell death in acute myeloid leukemia (AML) cells. In laboratory models of human AML, FHD-286 treatment reduced AML burden and significantly improved overall survival without inducing significant toxicity. In addition, researchers determined the efficacy of FHD-286 significantly improved survival when combined with venetoclax and decitabine compared to FHD-286 alone. FHD-286 works by blocking the activity of AML oncoproteins BRG1 and BRM, part of ATP-dependent chromatin remodeling complexes that move the histone proteins wrapped around DNA to make it more accessible. This is the first time that targeting chromatin remodeling complexes via BRG1 and BRM inhibition has been effective alone and in drug combinations against human AML cell models, and this therapy now is being tested in clinical trials at MD Anderson. Fiskus will present complete data and study results on April 16.   

Androgen receptor-directed therapy is examined for sarcoma subtype (Abstract 1196)
Desmoplastic small round cell tumors (DSRCT) are a rare, male-predominant, aggressive sarcoma subtype in the abdomen and pelvis that lack a molecularly targeted therapy. Prior research, led by Danh Truong, Ph.D., and Joseph Ludwig, M.D., implicated the androgen receptor as a key oncogenic driver of DSRCT and showed a potential therapeutic role for the anti-androgen therapy enzalutamide. Building upon those findings, the researchers used single-cell sequencing on nine patient tumors to identify three distinct DSRCT subtypes – epithelial, neuroendocrine, and hybrid – similar to known prostate cancer archetypes. This could be useful for identifying subsets of DSRCT patients most likely to benefit from anti-androgen therapies. Further, because neuroendocrine DSRCT and castrate-resistant prostate cancer have similar gene-expression profiles, novel treatment approaches developed for prostate cancer may yield unexpected benefits for DSRCT, an orphan pediatric cancer type in urgent need of better treatment options. Truong will present the results on April 16.   

Novel antibody-drug conjugate shows promise in osteosarcoma (Abstract 1202)
Osteosarcoma is the most common primary malignant bone tumor in adolescents and young adults, yet patient outcomes have not improved despite advances in treatment. Researchers led by Richard Gorlick, M.D., and Yifei Wang, M.D., identified CADM1 as a novel target for potential antibody drug conjugate (ADC) therapeutic approaches. The researchers developed an ADC using a monoclonal CADM1 antibody and an anti-tumor payload to damage osteosarcoma cells. Preliminary data showed encouraging responses and significantly prolonged survival in selected osteosarcoma models. In an analysis of 37 osteosarcoma tissue samples and 17 patient-derived xenografts, the researchers also found CADM1 was overexpressed in all osteosarcoma cells and minimally expressed in normal human tissue. This is the first ADC developed for osteosarcoma and results suggest it may be a viable treatment option, meriting further clinical trials. Wang will present the findings on April 16. 

Combination therapy improves outcomes in preclinical liver cancer models (Abstract 5745)
Patients with hepatocellular carcinoma (HCC), the most common primary liver cancer, respond poorly to current treatment options and have a low five-year survival rate, highlighting a critical need for novel therapeutic strategies. While the receptor tyrosine kinase MET is a known driver of HCC, MET inhibition alone has demonstrated limited clinical benefit due to upregulation of PD-L1 and subsequent immunosuppression. To investigate this, researchers led by Ricardo de Azevedo, Ph.D., and Michael Curran, Ph.D., evaluated the MET selective inhibitor capmatinib in vitro and combined it with anti-PD-1 checkpoint inhibitors in vivo. The combination limited tumor growth and improved survival across three HCC models. Further, the drugs increased proliferating and central memory CD8 T cells and protected against relapse better than PD-1 blockade alone. Even in an HCC model resistant to anti-PD-1 alone, the combination demonstrated significant and durable therapeutic benefit. This study highlights the potential of known MET and PD-1 inhibitors to inform combination strategies for future clinical trials. De Azevedo will present the findings on April 18.  

Study reports an aging heart in adolescent and young adult cancer survivors (Abstract 5759) 
Adolescent and young adult (AYA) cancer survivors often are exposed to treatments that can cause long-term complications that negatively impact organs, including the heart. To further study effects on the heart, researchers led by Michelle Hildebrandt, Ph.D., reviewed 424 echocardiograms and analyzed eight different echocardiographic functions from 127 Hodgkin lymphoma and sarcoma AYA cancer survivors treated with anthracycline and/or radiation. The researchers found significant differences in echocardiographic measures in AYA survivors compared to an untreated population. Among AYA survivors, 90% had more than one measure indicating their hearts were at least two decades older than their chronological age and an average of 4.2 measures related to accelerated cardiac aging. These results suggest the hearts of AYA cancer survivors are aging at a rate that is faster than their chronological age, meriting the use of these measures to identify at-risk patients for intervention to improve their outcomes. Hildebrandt will present the findings on April 18.

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