The Closing Keynote at the 2025 Hot Topics in Small Cell Lung Cancer (SCLC) centered around four decades of research in the field. Anish Thomas, MBBS, MD, began by inviting attendees to be inspired by the vision and scientific clarity that has defined the past 40 years of SCLC research, before introducing the keynote speaker, John D. Minna, MD.
This session and other meeting coverage is available on demand via Lung Cancer 360 for registered attendees.
Dr. Minna, Professor of Internal Medicine and Pharmacology at the University of Texas Southwestern Medical Center, Dallas, and Director of the Hamon Center for Therapeutic Oncology Research, was introduced as “one of the true pioneers of translational oncology,” before the term was even coined.
“The foundational work he did has produced one of the most widely used lung cancer models in the world,” Dr. Thomas said. “These models remain the cornerstone for discovery.”
Dr. Minna began by recounting his early-career experience working with Marshall Nirenberg, the 1968 Nobel Prize winner who “cracked” the genetic code.
“He was absolutely fearless, but he also stressed collaboration,” Dr. Minna said. “There will always be new things to do in [pursuit of] his love of science.”
He reflected on a past conversation with Dr. Nirenberg that shaped his perspective on science from that point on: Focus on identifying the problem you want to solve in your research, rather than solely on the available technology.
“My first advice to young people is [to] decide which problem [to solve]” Dr. Minna said. “Identify the biology or the clinical question, crystallize what you want to solve, and don’t focus on the technology.”
Dr. Minna noted that there are still knowledge gaps in SCLC research. These include early detection of SCLC, identifying if there are SCLC tumor acquired vulnerabilities that can be targeted with systemic therapies, and strategies to monitor patient responses to therapy.
He referenced three studies that may be useful in addressing these knowledge gaps.
The first study, conducted by Elisabeth Martinez, PhD, and Aiden Nguyen, PhD, identifies Jumonji histone demethylases, specifically KDM4A, as potential therapeutic targets in SCLC.1
Dr. Minna also highlighted the work of Rob Lewis, PhD, and Dianna Huisman, PhD, for their research on kinase suppressor of RAS 2 (KSR2), which demonstrated that KSR2 promotes self-renewal and clonogenicity of small-cell lung carcinoma.2
Lastly, Dr. Minna discussed research conducted by Ralph DeBerardinis, MD, PhD, which found that high glucose contribution to the TCA cycle is a feature of aggressive non-small cell lung cancer (NSCLC) in patients.3
This research suggests that glucose metabolism may be a predictor of tumor aggressiveness and metastasis in kidney, breast, and now, also in NSCLC. Dr. Minna indicated that this may now be an area worth exploring for SCLC.
“It’s a knowledge gap [if SCLC follows the same pattern] as these three others,” he said. “If it’s a totally different mechanism, that would be important to know as well.”
Despite advances in the field, 30% of primary tumors do not yet have a matching cell line or PDX, Dr. Minna noted.
“We don’t yet have a patient-derived model, PDX, CDX, or cell line to work with. Actually, the patients that we don’t yet have [models for] have much better prognosis,” said Dr. Minna. “And in the case of SCLC, the numbers lacking are maybe in the order of 5% to 10%.”
Dr. Minna concluded his presentation by reflecting on his decades-long journey to understand the 3p21.3 tumor suppressor genes.
“It’s [been] a 40-plus year chase to find 3p21.3 tumor suppressor genes in SCLC,” Dr. Minna said.
In his final thoughts, Dr. Minna expressed that it’s all about persistence in SCLC research, highlighting that allele loss occurs early in pathogenesis, even before dysplasia. He stressed the importance of knowing how early this can occur in a person at risk of developing SCLC, and that inactivation occurs across all lineage oncogene types and all MYC family expressions.
Additionally, he said that multiple genes had demonstrated dramatic tumor-suppressing activity. The genes associated with tumor suppression gene activity were predicted to have widely divergent functions, and few mutations were found.
“We thought there’d be one obvious pathway, but it’s hitting many things,” he said. “Epigenetic inactivation is common, which obviously both speaks to being able to reactivate things with some of the treatment approaches here, but also for blood monitoring too, for methylated alleles, multiple splicing isoforms,
Dr. Minna emphasized the importance of functional genomic technology to determine which genes matter and how they might be used to more effectively target SCLC. Similarly, international collaboration is essential to further advance research.
“All the new functional genomic technology is going to help us be able to put in now all 17 genes, cDNAs, or reactivate them and do dropouts in vivo to see which of these would be kicked out or not,” he said.
References
- 1. Nguyen A, Nuñez CG, Tran TA, Girard L, Peyton M, Catalan R, Guerena C, Avila K, Drapkin BJ, Chandra R, Minna JD, Martinez ED. Jumonji histone demethylases are therapeutic targets in small cell lung cancer. Oncogene. 2024 Sep;43(38):2885-2899. doi: 10.1038/s41388-024-03125-x. Epub 2024 Aug 18. PMID: 39154123; PMCID: PMC11405284.
- 2. Huisman, Dianna & Frodyma, Danielle & Svoboda, Robert & Vieira, Heidi & Chatterjee, Deepan & Skupa, Sydney & Askew, James & Fisher, Kurt & Kareta, Michael & Oliver, Trudy & Lewis, Robert. (2022). Kinase Suppressor of Ras 2 regulates small-cell lung carcinoma tumor propagating cells. 10.1101/2022.02.11.480157.
- 3. Ling Cai, Nia G. Hammond, Alpaslan Tasdogan, Massar Alsamraae, Chendong Yang, Robert B. Cameron, Peiran Quan, Ashley Solmonson, Wen Gu, Panayotis Pachnis, Mayher Kaur, Brianna K. Chang, Qin Zhou, Christopher T. Hensley, Quyen N. Do, Luiza Martins Nascentes Melo, Jessalyn M. Ubellacker, Akash Kaushik, Maia G. Clare, Isabel N. Alcazar, Katarzyna Kurylowicz, Joseph D. Marcuccilli, Gabriele Allies, Andrea Kutritz, Joachim Klode, Vijayashree Ramesh, Thomas J. Rogers, Aparna D. Rao, Hannah E. Crentsil, Hong Li, Fang Brister, Phyllis McDaniel, Xiaohong Xu, Bret M. Evers, Lauren G. Zacharias, Jessica Sudderth, Jian Xu, Thomas P. Mathews, Dwight Oliver, John D. Minna, John Waters, Sean J. Morrison, Kemp H. Kernstine, Brandon Faubert, Ralph J. DeBerardinis; High Glucose Contribution to the TCA Cycle Is a Feature of Aggressive Non–Small Cell Lung Cancer in Patients. Cancer Discov 1 April 2025; 15 (4): 702–716. https://doi.org/10.1158/2159-8290.CD-23-1319
