Pavlos Msaouel, Associate Professor of Genitourinary Medical Oncology at MD Anderson Cancer Center, shared on LinkedIn:
“Our work on panitumumab-based EGFR blockade in SMARCB1-deficient renal medullary carcinoma (RMC) is now published in AACR Journals Clinical Cancer Research.
RMC is an ultra-rare, lethal kidney cancer affecting predominantly young individuals of African descent with sickle cell trait. It is refractory to therapies approved for other renal cell carcinomas, and beyond first-line chemotherapy no strategy has achieved response rates above 20%.
We found that RMC expresses high levels of EGFR – but so do many tumors where EGFR inhibitors have failed. Expression is not dependency. What distinguishes RMC is how that expression arises: the tumor activates the EGFR locus through enhancer and promoter reprogramming rather than mutation or amplification, and simultaneously switches its ligand repertoire from EGF to epiregulin and amphiregulin. Notably, this is uncoupled from SMARCB1 loss itself as restoring SMARCB1 does not reduce EGFR, and other SMARCB1-deficient tumors express far less EGFR.
This matters because whereas tyrosine kinase inhibitors are effective mainly against mutant EGFR, wild-type EGFR-driven cancers respond to extracellular blocking antibodies. In our preclinical models, panitumumab markedly outperformed erlotinib, suppressed AKT and ERK signaling, and routed EGFR to lysosomes, producing a predominantly cytostatic effect. In a subsequent prospective multi-national registry of 26 heavily pretreated patients across ten centers, panitumumab-based therapy produced a 53.9% objective response rate including 15.4% complete responses, with median PFS of 5.8 months and median OS of 9.5 months.
These are non-randomized data but provide biological and clinical rationale for further prospective validation. For a disease no approved therapy, this is a strong foundation to build on. Grateful to every collaborator and, above all, to our patients.
The broader lesson about rare cancers is that the tools needed to find this dependency (immunohistochemistry, EGFR antibodies etc.) have existed for decades. What was missing was aggregated samples, purpose-built models, and a mechanism to act on the finding. That is a solvable problem, and it is worth solving for the many rare cancers still waiting.”
Title: Panitumumab-Based EGFR Blockade in SMARCB1-Deficient Renal Medullary Carcinoma: Preclinical Basis and Prospective Clinical Activity
Authors: Niki M. Zacharias, Eric S. Rupe, Xinyue Chen, Ritesh R. Kotecha, Damian T. Rieke, Bradley A. McGregor, Pedro Pesquera, Zhiyuan Yu, Abha Grover, Najat C. Daw, Emily Wang, Sze Wah Samuel Chan, Dorothea Douglas-Lindsay, Alice C. Fan, Eric M. Knoche, Christos E. Kyriakopoulos, Aly-Khan A. Lalani, Charlene M. Mantia, Amartej Merla, Martin H. Voss, Nicklas Pfanzelter, Sneha Ramakrishna, Neil M. Reaume, Tianyi Tang, Davis R. Ingram, Diana Shamsutdinova, Khalida M. Wani, Wei-Lien Wang, Alexander J. Lazar, Rahul A. Sheth, Priya Rao, Sandra L. Grimm, Cristian Coarfa, Rong He, Jing Qian, Fei Duan, Deepa Bisht, Pankaj K. Chauhan, Luigi Perelli, Giannicola Genovese, Liuqing Yang, Chunru Lin, Jose A. Karam, Ludovica La Posta, Eleonora Dondossola, Rafet Basar, Nadima Uprety, Katayoun Rezvani, Jianjun Gao, Linghua Wang, Luisa M. Solis Soto, Bora Lim, Nizar M. Tannir, Menuka Karki, Pavlos Msaouel
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