MD Anderson Research Highlights for October 20, 2021

Featuring discoveries in leukemia treatments and response predictors, screening disparities, pregnancies after cervical cancer treatment and a novel targeted therapy

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 new targeted therapy approaches for chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML), predicting survival following follicular lymphoma treatment, understanding how AML responds to checkpoint blockade therapy, identifying disparities in colorectal cancer screening, pregnancy outcomes following surgery for early-stage cervical cancer, and the discovery of a novel SHP2 targeted therapy.

Treatment of CLL with combined targeted agents can be discontinued for patients with confirmed undetectable MRD

Combined ibrutinib plus venetoclax treatment was shown to improve outcomes for patients with chronic lymphocytic leukemia (CLL). Continuous treatment with a BTK inhibitor, like ibrutinib, provides exceptional maintenance of disease control, but time-limited treatment options are needed. The phase II CAPTIVATE trial, led by William Wierda, M.D., Ph.D., assessed minimal residual disease (MRD)-based treatment discontinuation following completion of first-line, finite-duration ibrutinib plus venetoclax treatment in patients with CLL. For patients with confirmed undetectable MRD, the reported findings showed no difference in one-year disease-free survival rate (95% for both arms) between those randomized to continue single-agent ibrutinib or placebo. The results indicate the potential and expectation for meaningful durable remission off treatment following finite-duration therapy with this regimen. Learn more in Journal of Clinical Oncology

Combination therapy shows promise for AML expressing RUNX1 mutations

Patients with acute myeloid leukemia (AML) that expresses a RUNX1 mutation often have poorer clinical outcomes than those with wild-type RUNX1. In laboratory-based mechanistic studies led by Kapil Bhalla, M.D., AML cells expressing mutant RUNX1 were more sensitive to the protein translation inhibitor omacetaxine and the BCL2 inhibitor venetoclax. Therefore, Bhalla and colleagues explored combination therapy with omacetaxine and venetoclax or a BET inhibitor. Compared to single-agent therapy, the combination treatment showed synergistic anti-AML effects in vivo, improving survival in laboratory models. These findings suggest that omacetaxine-based combination therapies may be effective against AML with RUNX1 mutations. Learn more in Blood

Validating disease progression as a clinical predictor of survival in follicular lymphoma

Previous trials and studies have suggested that patients with follicular lymphoma (FL) whose disease progresses within 24 months of front-line chemoimmunotherapy have poor outcomes. Christopher Flowers, M.D., and colleagues conducted a pooled analysis of 13 randomized clinical trials of FL patients to validate progression of disease after 24 months (abbreviated as POD24) and analyze it in relation to clinical outcomes. The pooled analysis found that POD24 following chemoimmunotherapy was associated with poor overall survival, and it identified clinical predictors, like elevated β2-microglobulin and high Follicular Lymphoma International Prognostic Index (FLIPI) risk score, of disease progression. These findings may be used to build future models, incorporating clinical and molecular predictors of POD24 to better predict patients’ outcomes. Learn more in Blood

Understanding response to PD-1 blockade treatment in acute myeloid leukemia

Checkpoint blockade-based therapies tend to produce only moderate responses in patients with acute myeloid leukemia (AML). To evaluate whether biomarkers of response or resistance could be identified, a team led by Hussein Abbas, M.D., Ph.D., Andy Futreal, Ph.D., and Naval Daver, M.D., conducted paired single-cell RNA analysis and TCR profiling of bone marrow cells in patients with AML who responded and then relapsed or did not respond following azacitidine and PD1 inhibitor therapy. They demonstrated that the subsets of T cells related to AML were very heterogeneous after PD-1 blockade-based treatment; T cell repertoires expanded in patients whose disease remained stable or responded to treatment and contracted in patients whose disease was resistant to treatment. These findings indicate that adaptive T cell plasticity affects how AML responds to PD-1 blockade-based therapies and may help in developing future immune strategies for AML. Learn more in Nature Communications.

Women living in rural areas less likely to be screened for colorectal cancer 

Cancer screenings have been shown to save lives, but disparities persist across certain demographics. Research has shown that cancer mortality rates remain higher in rural populations, which have higher incidences of cancer types that are preventable through regular screening, compared to urban populations. In this study, Sanjay Shete, Ph.D., and colleagues from the Rural Workgroup of the NCI Population Health Assessment in Cancer Center Catchment Areas Initiative, analyzed breast and colorectal cancer screening rates among 2,897 women from 11 states. They found significant differences in adherence to colorectal cancer screening, with 82% of women in urban areas up to date on screening, compared to 78% of women in rural areas. However, both groups were equally likely to be up to date on breast cancer screening (81%). The findings indicate an opportunity for improved public health interventions. Learn more in JAMA Network Open

First pregnancy after fertility-sparing surgery for early-stage cervical cancer patients had higher odds of preterm delivery

Most patients with cervical cancer will be diagnosed around reproductive age, and an increasing number of women with early-stage disease seek fertility-sparing options. These surgical options — cervical conization, loop electrosurgical excision procedure (LEEP) and trachelectomy — have been widely accepted in select patients; however, because fewer than half of patients attempt to conceive, the obstetric risks have not yet been fully explored. In a population-based study, Alejandro Rauh-Hain, M.D., and a team of researchers evaluated the outcomes of the first pregnancy after fertility-sparing surgery in patients with early-stage cervical cancer. The researchers found that for women who conceived at least three months after undergoing cervical conization or LEEP for cervical cancer, the odds of preterm birth and neonatal morbidity were doubled. However, pregnancies after fertility-sparing surgery for cervical cancer did not have an increased risk of preterm birth before 32 weeks of gestation, stillbirth, cesarean delivery, growth restriction or severe maternal morbidity. Learn more in Obstetrics & Gynecology.

Novel SHP2 targeted therapy effective in early laboratory studies

The SHP2 protein (Src homology 2 domain-containing phosphatase), which sits at the intersection of multiple oncogenic signaling pathways, plays a critical role in cancer development across many tumor types. Evidence suggests that SHP2 also suppresses the anti-tumor immune response. Through an ongoing strategic collaboration, MD Anderson’s Therapeutics Discovery division and BridgeBio Pharma, Inc. are advancing SHP2 inhibitors, including the launch of a clinical trial for BBP-398 in 2020. Complementing those efforts, a team led by Barbara Czako, Ph.D., and Philip Jones, Ph.D., report the discovery of IACS-15414, a potent inhibitor of SHP2. In this preclinical study, IACS-15414 displayed an optimal pharmacokinetic profile in preclinical models as an oral therapy with no off-target effects. IACS-15414 also was effective at blocking activity of the MAPK signaling pathway and suppressing tumor growth in cancer models with activated receptor tyrosine kinase (RTK) signaling or mutant KRAS. Learn more in the Journal of Medicinal Chemistry

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Read below to catch up on recent MD Anderson press releases.