Donald W. Kufe, MD
Distinguished Physician, Dana-Farber
Professor of Medicine, Harvard Medical School
Donald Kufe, MD, Distinguished Physician at Dana-Farber and Professor of Medicine at Harvard Medical School, has spent decades investigating the MUC1-C protein, one of cancer’s most elusive drivers, and has gleaned essential insights into how certain cancers grow, evade treatment, and resist immune attack. Today, his lab is translating that foundational research into a new therapeutic strategy—developing small molecule inhibitors aimed at disabling MUC1-C’s cancer-promoting functions. This work has been selected for funding by the Dana-Farber Accelerator.
Kufe first identified the MUC1 gene and revealed that the encoded C-terminal subunit, MUC1-C, acts as an oncoprotein. It disrupts normal cell architecture, activates growth-promoting signals, and fuels inflammation—all of which contribute to cancer progression and resistance to therapy. “MUC1-C drives malignant transformation across pan-cancers,” Kufe explains. “We’re now working to block its activity with small molecules.”
A New Therapeutic Strategy
The Kufe Lab is focused on designing small molecules that target the intracellular domain of MUC1-C—the region responsible for its oncogenic signaling. Unlike antibody-based therapies or CAR T-cell approaches directed against proteins on the cancer cell surface, these small molecules are intended to work inside the cell, where MUC1-C exerts its effects.
This approach represents a shift in strategy, offering a potentially more direct way to interfere with MUC1-C’s role in cancer biology. By focusing on the intracellular domain, researchers hope to address mechanisms of resistance and tumor survival that are not targeted by existing therapies.
Why MUC1-C Matters
MUC1—and particularly MUC1-C—is overexpressed in at least 8–10 major tumor types, including breast, lung, pancreatic, ovarian, colorectal, prostate, gastric, renal, and head and neck cancers. Together, these represent the majority of adenocarcinomas and many aggressive solid tumors. Some estimates suggest that MUC1 is overexpressed in more than 80% of adenocarcinomas, translating to millions of cases worldwide. This is significant, since MUC1-C supports cancer cell survival by activating inflammatory pathways and promoting a stem-like state that makes tumors harder to treat. It also contributes to resistance against targeted therapies, such as those aimed at EGFR and HER2.
Importantly, MUC1-C is linked to processes like epithelial-mesenchymal transition (EMT), epigenetic reprogramming, and self-renewal—hallmarks of aggressive and treatment-resistant cancers. These features make it a compelling target for drug development, especially in cancers where conventional therapies have limited impact.
Translating Discovery into Impact
The project was initially conducted by Atrayee Bhattacharya, PhD, who oversaw early development efforts. Mai Moriya has now taken over performing these studies, which has completed its SPARK-funded phase and is advancing toward further preclinical development.Specifically, the team is working to refine its approach and move toward testing in relevant cancer xenograft models. While details of the molecules under development remain confidential, the Lab’s goal is to identify inhibitors that can be used across multiple cancer types and potentially in combination with other therapies.
Complementing Existing Therapies
Other therapies targeting MUC1-C—such as antibody-drug conjugates and CAR T-cell therapies—are in various stages of clinical and pre-clinical development. These approaches primarily focus on the extracellular domain of the protein. Small molecule inhibitors offer a complementary strategy, one that could be used alongside existing treatments or in cancers where immune-based approaches are less effective.
Given MUC1-C’s role in maintaining the cancer stem cell state and promoting resistance, these inhibitors could have broad applications. They may be especially valuable in cancers that are refractory to current therapies, offering a new option for patients with limited treatment choices.
Looking Ahead
With growing recognition of MUC1-C’s role in cancer resistance and progression, the development of targeted small molecules represents a critical step forward. For patients with few options, this research could open the door to more effective and personalized therapies.
Kufe’s decades-long commitment to understanding MUC1-C is now converging with a translational push to bring new treatments to the clinic. “We’ve spent years defining the biology,” he says. “Now we’re focused on turning that knowledge into therapies that can make a difference for patients.”
Team Members