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From Discovery to Delivery: Charting Progress in Gynecologic Oncology, hosted by Ursula A. Matulonis, MD, brings expert insights into the most recent breakthroughs, evolving standards, and emerging therapies across gynecologic cancers. Dr Matulonis is chief of the Division of Gynecologic Oncology and the Brock-Wilcon Family Chair at the Dana-Farber Cancer Institute, as well as a professor of medicine at Harvard Medical School, both in Boston, Massachusetts. In this episode, Dr Matulonis was joined by Elizabeth H. Stover, MD, PhD, a physician at Dana-Farber Cancer Institute and an assistant professor of medicine at Harvard Medical School. Together, they explored the biology and therapeutic relevance of the RAS/MAP kinase pathway in gynecologic cancers. Dr Stover began by explaining that the RAS/MAP kinase pathway is a well-established oncogenic signaling cascade that regulates cancer cell proliferation, survival, and invasion. Advances in drug development are now making it possible to target multiple points along this pathway, including RAS itself, once considered “undruggable.”Drs Matulonis and Stover emphasized that RAS/MAP kinase pathway alterations are relatively common across gynecologic malignancies, occurring in at least 20% of cases overall. Certain disease subtypes have particularly high prevalence, including low-grade serous ovarian cancer, mucinous ovarian cancer, and subsets of endometrial and cervical cancers. Clinically, activation of this pathway is generally associated with more aggressive disease and reduced sensitivity to conventional chemotherapy, although nuances exist. The conversation also explored emerging therapeutic strategies targeting this pathway. Early developmental success with MEK inhibitors—such as trametinib (Mekinist), selumetinib (Koselugo), and binimetinib (Mektovi)—has translated to meaningful clinical benefit, particularly in low-grade serous ovarian cancer. More recently, combination approaches have shown promise, including the dual RAF/MEK inhibitor avutometinib paired with the FAK inhibitor defactinib (Avmapki Fakzynja Co-pack). This combination addresses adaptive resistance mechanisms and has generated improved response rates and disease control, leading to its May 2025 FDA approval in this setting.Looking ahead, Dr Stover highlighted the development of direct RAS inhibitors as one of the most exciting advances in oncology. Dr Stover concluded by outlining key areas of ongoing research, including understanding differential sensitivity across tumor subtypes, identifying mechanisms of resistance, and optimizing combination strategies.
A new editorial paper was published in Oncotarget's Volume 14 on June 12, 2023, entitled, “Are cis-spliced fusion proteins pathological in more aggressive luminal breast cancer?” A vast majority of breast cancers (~70%) are estrogen receptor-alpha positive (ER+), for which endocrine therapy is the common treatment. However, recurrence often occurs leading to tumor progression, metastasis and eventually patient death, and the underlying molecular mechanisms remain poorly understood. In this new editorial, researchers Chia-Chia Liu and Xiao-Song Wang from the University of Pittsburgh discuss their recent study regarding recurrent gene fusions — hallmarks of some cancers that resulted either from chromosomal rearrangements or from cis- or trans-splicing. “Importantly, selected oncogenic fusions have been matched with effective targeted therapy in several solid tumors. For instance, EML4-ALK, one of the most important oncogenic driver genes of non-small cell lung cancer (NSCLC) uncovered in recent years.” In addition to gene fusions resulting from genomic rearrangements, a read-through SLC45A3-ELK4 fusion transcript has been identified in prostate cancer which is associated with disease progression and metastasis. Although the whole genome and RNA sequencing provide an effective way to detect fusion genes, the downstream identification and validation of fusion genes or their products in solid tumors remains a major challenge. Through analysis of RNA-seq data from TCGA, the authors of this editorial and their co-authors recently identified a neoplastic fusion transcript RAD51AP1-DYRK4 in luminal B breast cancer (~17.5%) showing higher ki67 expression which is an indication of aggressive clinical characteristics. “In this study, we examined the utility of MEK inhibitor trametinib (Mekinist) currently used for treating melanoma with BRAF mutations, in blocking the MEK-ERK signaling driven by RAD51AP1-DYRK4 fusion. Interestingly [...] RAD51AP1-DYRK4 may endow sensitivity to MEK inhibition in luminal B breast cancer [13]. To our knowledge, this is one of the few non-traditional fusions generated by read-through events in the absence of DNA rearrangement that play an important role in tumorigenesis.” DOI - https://doi.org/10.18632/oncotarget.28438 Correspondence to - Xiao-Song Wang - xiaosongw@pitt.edu Sign up for free Altmetric alerts about this article - https://oncotarget.altmetric.com/details/email_updates?id=10.18632%2Foncotarget.28438 Subscribe for free publication alerts from Oncotarget - https://www.oncotarget.com/subscribe/ Keywords - cancer, luminal B breast cancer, RAD51AP1-DYRK4, MEK inhibitor, chimerical transcript About Oncotarget Oncotarget (a primarily oncology-focused, peer-reviewed, open access journal) aims to maximize research impact through insightful peer-review; eliminate borders between specialties by linking different fields of oncology, cancer research and biomedical sciences; and foster application of basic and clinical science. To learn more about Oncotarget, please visit https://www.oncotarget.com and connect with us: SoundCloud - https://soundcloud.com/oncotarget Facebook - https://www.facebook.com/Oncotarget/ Twitter - https://twitter.com/oncotarget Instagram - https://www.instagram.com/oncotargetjrnl/ YouTube - https://www.youtube.com/@OncotargetJournal LinkedIn - https://www.linkedin.com/company/oncotarget Pinterest - https://www.pinterest.com/oncotarget/ Reddit - https://www.reddit.com/user/Oncotarget/ Media Contact MEDIA@IMPACTJOURNALS.COM 18009220957
FDA Drug Information Soundcast in Clinical Oncology (D.I.S.C.O.)
Listen to a soundcast of the March 16, 2023, FDA approval of Tafinlar (dabrafenib) for pediatric patients with low-grade glioma with a BRAF V600E mutation
FDA Drug Information Soundcast in Clinical Oncology (D.I.S.C.O.)
Listen to a soundcast of the June 22nd 2022 FDA approval of Tafinlar (dabrafenib) for in combination w/trametinib (brand name Mekinist) for unresectable or metastatic solid tumors with BRAF V600E mutation.
Dr. Vicki Goodman, VP, Therapeutic Area Head, Late Stage Oncology at Merck discusses the recent Phase 3 KEYNOTE-204 positive EU CHMP opinion for expanded approval of KEYTRUDA® (pembrolizumab) for the treatment of relapsed or refractory classical Hodgkin lymphoma (cHL) that meet certain criteria. Vicki Goodman, MD, is Vice President, Therapeutic Area Head for Late Stage Oncology at Merck. In this role, she oversees Merck’s portfolio in lung cancers, women’s cancers, hematology, and head and neck cancer. Vicki joined Merck from Bristol-Myers Squibb where most recently she was VP, Head, Clinical Development Center of Excellence. She is a hematologist and medical oncologist with 15 years of drug development experience in both government and industry. Vicki trained in internal medicine and hematology/oncology at the University of Michigan. She then served as a medical officer at FDA for over two years and subsequently worked at GlaxoSmithKline for eight years. While at GSK, Vicki took on roles of increasing responsibility and worked on a range of projects including pazopanib (Votrient) and dabrafenib (Tafinlar), alone and in combination with trametinib (Mekinist). She also led the development of several early to mid-stage oncology drug candidates. She joined BMS in January 2015 as Vice President, Development Leader for Opdivo/Yervoy in Melanoma and GU tumors. In this role, she oversaw the approval of the first I-O combination (Opdivo and Yervoy) in advanced melanoma, approval of Opdivo in adjuvant melanoma, RCC and bladder cancer, and the initiation of several key phase 3 programs. In July 2017, she was appointed to lead BMS new asset development teams, overseeing a portfolio of experimental assets between proof of concept and first regulatory approval. Vicki served as a senior advisor to the BMS women’s network, has lectured and served as a panelist in women’s oncology leadership forums including at the University of Pennsylvania Perelman School of Medicine. Vicki was profiled in Fierce Women in Biopharma in 2016 and recognized for her contributions to oncology development by Gilda’s Club NYC in 2017.
In the rapidly evolving treatment landscape for advanced melanoma, medical oncologists now have a suite of treatments to choose from for their patients. In this engaging podcast, A/Prof Menzies interviews fellow Medical Oncologist A/Prof Carlino on the rationale behind their clinical decision making when it comes to choosing the most appropriate therapy for their patients, including sequencing and combination therapies. They also take a deeper dive into treatment toxicities and how to manage them for targeted and immune therapies.This podcast is suitable for Oncologists, Oncology Nurses and other healthcare professionals.
A study released at ASCO 2015 showed that the BRAF V600E mutation had a high response rate to combination therapy Tafinlar (dabrafenib) plus Mekinist (trametinib), which led the doctors to agree that BRAF testing in lung cancer should become commonplace.
A study released at ASCO 2015 showed that the BRAF V600E mutation had a high response rate to combination therapy Tafinlar (dabrafenib) plus Mekinist (trametinib), which led the doctors to agree that BRAF testing in lung cancer should become commonplace.
A study released at ASCO 2015 showed that the BRAF V600E mutation had a high response rate to combination therapy Tafinlar (dabrafenib) plus Mekinist (trametinib), which led the doctors to agree that BRAF testing in lung cancer should become commonplace.
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