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UrduRecent developments include results from a small-molecule inhibitor of oxidative phosphorylation, early antitumor response from a targeted therapy in patients with liposarcoma, the identification of epigenetic therapeutic targets in small cell lung cancer, a prognostic tool to help inform breast cancer therapy recommendations, a study of disparities in early mortality for adolescents and young adults with cancer, and a potential approach to improve treatment response in soft-tissue sarcomas.
Clinical trials of MD Anderson-developed therapy bring new insights to targeting oxidative phosphorylation Certain tumors become dependent on the oxidative phosphorylation (OXPHOS) metabolic pathway for cellular energy production, making it an attractive target for new cancer therapies. However, clinical benefit with OXPHOS inhibitors has not yet been realized. Scientists in the Institute for Applied Cancer Science and the TRACTION platform, both part of MD Anderson’s Therapeutics Discovery division, developed the OXPHOS inhibitor IACS-10759, a small-molecule targeting the group of OXPHOS proteins known as Complex I. Timothy Yap, M.B.B.S., Ph.D., Naval Daver, M.D., Philip Jones, Ph.D., Joseph Marszalek, Ph.D., and colleagues evaluated IACS-10759 in two Phase I trials for advanced solid tumors and advanced acute myeloid leukemia. The treatment achieved transient target inhibition, but frequently was associated with neurotoxicity and elevated blood lactate levels. As a result, both trials were discontinued. The results reveal important insights for the field, providing guidance and caution for future development of OXPHOS inhibitors. Learn more in Nature Medicine.
MDM2 inhibitor milademetan shows early evidence of antitumor activity
The MDM2 protein is a negative regulator of the p53 tumor suppressor protein, and the MDM2 inhibitor milademetan aims to restore the p53’s antitumor activity. In a first-in-human Phase I trial led by David S. Hong, M.D., milademetan showed evidence of antitumor activity, especially in dedifferentiated liposarcoma. The primary objective in the study was to determine the recommended Phase II dose and schedule, which was found to be 260 mg once daily for three of 14 days. More continuous regimens were associated with on-target toxicities. In 107 patients, the overall disease control rate (DCR) was 45.8% and the median progression-free survival (PFS) was four months. In the subgroup with dedifferentiated liposarcomas, the DCR was 58.5% and median PFS was 7.2 months. The most common grade 3-4 drug-related adverse events were thrombocytopenia (29%), neutropenia (15%) and anemia (13.1%). Phase II and Phase III trials evaluating milademetan currently are underway. Learn more in the Journal of Clinical Oncology.
SET2,3 test added independent information to recurrence score for node-positive breast cancer The 21-gene breast recurrence score (RS) is used to decide whether chemotherapy would provide additional benefit to hormone therapy alone for patients with lymph node-positive breast cancer. A different test (SET2,3 index) developed by Fraser Symmans, M.D., predicts the cancer’s sensitivity to endocrine therapy relative to baseline prognostic characteristics. Researchers from the National Clinical Trials Network’s Southwest Oncology Group (SWOG) tested whether the SET2,3 index added predictive or prognostic information to the RS using samples from the SWOG S8814 trial, which evaluated adjuvant anthracycline-based chemotherapy followed by tamoxifen hormone therapy for five years compared with tamoxifen alone. While SET2,3 index did not predict benefit from anthracycline-based chemotherapy, it had no correlation with RS and their combined results significantly improved prognostic assessment. Further work is needed to determine when and how multiple assays should be used in breast cancer treatment and to evaluate SET2,3 index with contemporary endocrine-based treatments. Read more in the Journal of Clinical Oncology.
Preclinical study identifies potential therapeutic targets in small cell lung cancer Small cell lung cancer (SCLC) is highly malignant and has no currently approved targeted therapies. The CARM1 enzyme plays a role in promoting gene transcription, and its inhibition improves anti-tumor activity in various other cancers. However, its downstream targets are not well understood, and its therapeutic value has not been tested in SCLC. The NFIB transcription factor, which often is amplified in SCLC, is a substrate for CARM1. To characterize this relationship, researchers led by Guozhen Gao, Ph.D., Simone Hasumann, Ph.D., Pawel Mazur, Ph.D., and Mark Bedford, Ph.D., used in vivo SCLC models to show that CARM1 is a transcriptional coactivator for NFIB and affects gene expression through methylation at a single site. Losing NFIB methylation via CARM1 inhibition or NFIB mutation blocked tumor progression in these models. This study highlights NFIB amplification and CARM1 as drivers of rapid SCLC onset, meriting further investigation as therapeutic targets. Learn more in Nature Communications.
Sequential targeting of cell cycle to prime retinoblastoma and induce DNA damage could improve anti-tumor response in sarcomas Soft tissue sarcomas (STS) are rare cancers that form in tissues surrounding body organs, and there currently is a lack of effective treatment options. Reactivating the retinoblastoma (Rb) pathway with CDK4/6 inhibitors has been successful in other cancers, but these inhibitors have not shown much efficacy in STS as monotherapy or when combined with chemotherapy. Chemotherapy agents work by targeting a later stage of the cell cycle, making them inefficient if concurrent CDK4/6 inhibitors have already arrested cell cycle progression. Therefore, researchers led by Khandan Keyomarsi, Ph.D., evaluated a novel two-step sequential treatment approach. They first administered the CDK4/6 inhibitor abemaciclib to prime Rb-positive tumor cells, then removed the drug and allowed a recovery period, permitting the cell cycle to progress before giving chemotherapy. This sequential process, which can be non-invasively monitored in real time, effectively killed tumors in in vitro and in vivo, highlighting its therapeutic and clinical translation potential. Learn more in Cancer Research.
Recent awards and honors
Four MD Anderson researchers were elected members of the American Society for Clinical Investigation:
- Courtney DiNardo, M.D., associate professor of Leukemia
- Anirban Maitra, M.B.B.S., professor of Pathology and Translational Molecular Pathology
- Katy Rezvani, M.D., Ph.D., professor of Stem Cell Transplantation & Cellular Therapy
- Hussein Tawbi, M.D., Ph.D., professor of Melanoma Medical Oncology
In case you missed it
Read below to catch up on recent MD Anderson press releases.
- MD Anderson and Federation Bio announce collaboration to develop novel microbiome treatment for patients with immunotherapy-resistant cancers
- Three MD Anderson researchers elected AAAS Fellows
- Targeted therapy momelotinib provides significant symptom and anemia improvements in patients with myelofibrosis
- MD Anderson EGFR Classification licensed by BostonGene and Tempus to provide new insight on atypical mutations in lung cancer
- MD Anderson’s Jennifer Wargo receives TAMEST O’Donnell Award for pioneering microbiome research
- Scientists develop novel mRNA delivery method using extracellular vesicles
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