Recent developments at MD Anderson offer insights into expanding the use of FGFR inhibitors, maintaining radiation therapy as standard of care for locally recurrent endometrial cancer, an antibody-drug conjugate for breast cancer, an integrated method of examining protein shapes to optimize drug discovery, a novel CRISPR screening platform to identify functionally redundant genes, a secretory protein target in cancers with chromosome 3q amplifications, optimizing the use of stereotactic radiosurgery for patients with brain metastases, and an evaluation of factors associated with trial enrollment for patients with Non-Hodgkin lymphoma.
Trial shows FGFR inhibitor pemigatinib may benefit a broader patient population
Fibroblast growth factor receptor (FGFR) inhibitors are promising therapeutic options in multiple cancer types, but first-generation FGFR inhibitors have poor target selectivity and side effects that limit their clinical applications. Pemigatinib is a more selective FGFR inhibitor approved for use in refractory cholangiocarcinoma and myeloid/lymphoid neoplasms with FGFR1 rearrangements. In the Phase II FIGHT-207 trial, led by Jordi Rodon, M.D., Ph.D., researchers evaluated pemigatinib in previously treated patients with advanced FGFR-altered solid tumors. The drug achieved responses across multiple tumor types, with the highest response rate (26.5%) in patients with FGFR1-3 fusions, including glioblastoma and pancreatic cancers not previously known to respond to FGFR inhibitors. Certain co-occurring mutations also correlated with patient responses. For example, BAP1 mutations were associated with higher response rates, while TP53 alterations were linked with lower rates. These findings support possible expansion of the indications for FGFR inhibitors. These data were first presented at the American Association for Cancer Research (AACR) Annual Meeting 2023. Learn more in Nature Medicine.
Standard-of-care radiation therapy is sufficient for locally recurrent endometrial cancer
Most patients with endometrial cancer are cured with a hysterectomy, but some have recurrences in lymph nodes and/or the vagina that typically are treated with external beam radiation therapy and brachytherapy. Researchers led by Ann Klopp, M.D., Ph.D., sought to examine if adding chemotherapy could improve progression-free survival (PFS) in these patients. The trial randomized 165 patients with locally recurrent pelvic endometrial cancer to receive either radiation alone or in combination with cisplatin chemotherapy. The study found no significant improvement in median PFS with the combination treatment, and toxicity rates were higher in this group compared to those receiving radiation alone. After three years, 73% of patients treated definitively with radiation and 62% of patients treated with chemoradiation were alive and free of disease progression. These results suggest that radiation alone is sufficient for treating localized recurrences of endometrial cancer and remains the recommended treatment for this patient population. Learn more in the Journal of Clinical Oncology.
Antibody-drug conjugate demonstrates clinical activity, manageable safety profile in patients with advanced breast cancer
Patients with metastatic hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) and triple-negative breast cancer (TNBC) face five-year survival rates, necessitating more effective treatments. Datopotamab deruxtecan (Dato-DXd) is an antibody-drug conjugate targeting TROP2, a surface protein found in over 75% of breast cancers. In the Phase I TROPION-PanTumor01 study, led by Funda Meric-Bernstam, M.D., Dato-DXd showed promising activity in a heavily pretreated population of 85 patients with HR+/HER2- cancers and TNBC, with objective response rates of 26.8% and 31.8%, respectively. Stomatitis was the most common side effect, occurring at grade three or higher in 9.8% of HR+/HER2- patients and 11.4% of TNBC patients. All patients experienced side effects, with grade three or above in 41.5% and 52.3% of patients with HR+/HER2- and TNBC, respectively. Only five patients discontinued treatment. Based on these results, Phase III trials of Dato-DXd are underway. Learn more in the Journal of Clinical Oncology.
Drug discovery method integrates time-resolved X-rays to examine protein shapes
Small molecule drug discovery methods seek to identify candidates that interact with protein targets, but often overlook how drug binding impacts protein structure over time. Researchers led by Chris Brosey, Ph.D., and John Tainer, Ph.D., developed a novel drug discovery method that combines classic fragment screening with a technique for mapping protein structures, called time-resolved, high throughput small-angle X-ray scattering (TR-HT-SAXS). They tested this method on the mitochondrial protein AIF by monitoring how a library of small molecules alters AIF structural states over time. In the resulting dataset, researchers identified specific chemical fragments that cause two AIF proteins to bind and activate. Follow-up biochemical and structural experiments validated these findings, suggesting this drug discovery workflow is capable of identifying small molecules that bind and modify protein structure in desired ways. This approach could lead to higher specificity in chemical hits and the ability to target natural rate-limiting steps in cells. Learn more in Nature Chemical Biology.
Improved CRISPR screening platform can better target functionally redundant genes
CRISPR screens can help find potential biomarkers and mechanisms of treatment sensitivity or resistance, but they often fail to identify functionally redundant genes. Researchers led by Traver Hart, Ph.D., developed a new CRISPR/Cas12a platform called “in4mer,” which uses four independent guide RNAs to target both single genes and gene pairs, or paralogs, with redundant functions. Using the in4mer platform, the researchers created a more sensitive and efficient CRISPR library capable of targeting all single genes and more than 4,000 paralogs. The platform performed well in various cancer cells, demonstrating its ability to accurately identify essential genes and synthetic lethal paralogs while substantially reducing the effort needed. This platform could lead to new insights into genetic relationships and the development of therapeutic strategies. Learn more in Nature Communications.
Targeting secretory protein shows promise for chromosome 3q-amplified cancers
Cancer cells have increased secretion of cellular materials that can drive tumor progression, but the underlying mechanisms are not well understood. By examining a specific region on chromosome 3q that is often amplified in cancer cells, researchers led by Jonathan Kurie, M.D., identified a key protein – GOLIM4 – involved in protein secretion and transport. Reducing GOLIM4 disrupts the complex and blocks secretion, slowing down tumor progression. To maintain homeostasis, GOLIM4 also binds excess intracellular manganese (Mn) and induces its degradation, highlighting GOLIM4 as a potential target and Mn as a potential targeted therapy. Co-amplification of another gene increased Mn influx into the Golgi apparatus and resulted in faster degradation of GOLIM4. Collectively, these findings suggest that targeting this secretory pathway with Mn could inhibit the progression of 3q-amplified cancers. Learn more in the The Journal of Clinical Investigation.
Study characterizes stereotactic radiosurgery treatment response in brain metastases
Patients with brain metastases have a poor prognosis, due in part to challenges with effectively delivering treatments through the blood-brain barrier. Stereotactic radiosurgery (SRS) is used to treat small brain metastasis, but it has variable responses. To better understand outcomes, researchers led by Chibawanye Ene, M.D., Ph.D., performed a retrospective analysis in 1,733 lesions from 1,095 patients with three or fewer treatment-naïve small brain metastases who received framed SRS over a 25-year period. The results showed these brain metastases did not all respond to SRS in the same way. Tumor size – especially those larger than 1.5 cm – and melanoma histology, in particular, were associated with higher local treatment failure rates. These findings suggest that tumor-intrinsic factors should be considered to optimize SRS treatment guidelines and improve outcomes for patients with small brain metastases. Learn more in Nature Communications.
Age and diagnosis are predictors of participation in non-Hodgkin Lymphoma clinical trials
Previous studies have suggested certain groups, such as older patients and racial/ethnic minorities, are underrepresented in clinical trials. To understand the impact of demographic and socioeconomic factors on non-Hodgkin lymphoma (NHL) trial participation, researchers led by Chijioke Nze, M.D., conducted a retrospective analysis of 3,146 adult patients with NHL treated at MD Anderson. They investigated the association between trial participation and race/ethnicity, travel distance and neighborhood socioeconomic status. The researchers found that trial participation decreased with age, and specific NHL diagnoses were associated with different participation levels. Trial participation was not predicted by race, gender or neighborhood socioeconomic variables. However, there were noticeably lower participation rates among patients with lower socioeconomic status at an individual level. This comprehensive evaluation of clinical enrollment provides insights into participation barriers to overcome in certain patient populations. Learn more in Blood Advances.
Awards and honors
Christopher Logothetis, M.D., professor of Genitourinary Medical Oncology, Guillermo Garcia-Manero, M.D., professor of Leukemia, and Kelly Hunt, M.D., chair of Breast Surgical Oncology, were inducted into the 2024 Class of the Giants of Cancer Care recognition program In case you missed it
Read below to catch up on recent MD Anderson press releases.
Increasing doses of varenicline or nicotine replacement helps persistent smokers quit MD Anderson researcher Sharon Dent elected to prestigious National Academy of Sciences MD Anderson and Pan American Health Organization join forces to support cancer prevention and control in the Americas MD Anderson and Replay announce FDA clearance of IND application for first-in-class PRAME-targeted TCR NK cell therapy for hematological malignancies Cancer screening rates are significantly lower in U.S. Federally Qualified Health Centers MD Anderson and RUSH unveil RUSH MD Anderson Cancer Center Read this press release in the MD Anderson Newsroom.
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