By John Schardt and Steven Jay
Despite substantial effort and innovation in oncology therapeutic development, cancer remains a leading cause of death worldwide. HER3, a member of the human epidermal growth factor receptor family, has emerged as a critical target for cancer therapy. This receptor tyrosine kinase is implicated in the progression of a variety of cancers—including ovarian, prostate, lung, and breast—and compensatory signaling through HER3 is a key mechanism to cancer cell resistance to a variety of FDA-approved therapies. Numerous monoclonal antibody-based strategies against HER3 are in clinical development, but there are currently no FDA-approved HER3-targeted therapeutics.
Despite tremendous advances in antibody-based therapeutics in general, even the most impactful of these drugs are ineffective in a significant proportion of patients. For example, it has been reported that HER2-targeted therapies typically show efficacy only in subsets of patients with HER2-overexpressing tumors. Thus, new innovative molecular approaches to improve targeted cancer therapy would address a crucial clinical need.
HER3 sequestration by engineered multivalent ligands, the focus of my doctoral thesis research, represents a novel strategy to treat HER3-related malignancies. This approach involves locking HER3 into non-signaling homotypic interactions and takes advantage of the fact that HER3 is generally thought to be incapable of initiating signaling without partnering with another receptor type, such as other members of the epidermal growth factor receptor family. Leveraging this strategy, we initially engineered multivalent ligands—multiple HER3 binding domains connected by flexible spacer domains—to sequester HER3. Our molecular design is predicated on the principles of multivalency, whereby simultaneous molecular recognition events can enhance therapeutic efficacy by means of improved binding kinetics, selectivity and differential receptor trafficking. Our initial generation of ligands utilized a protein, Neuregulin-1B, as the HER3 binding domain, and these molecules successfully limited proliferation of numerous cancer cell types. We have now developed multiple classes of ligands using this approach, including our recent production of multivalent antibody-mimetic HER3-binding proteins (affibodies) that can potently induce HER3 degradation; whereas, control monovalent ligands do not.
These latest findings have spurred our continued interest in optimized multivalent ligand configurations. We are currently pursuing combination therapy approaches involving these ligands and identifying molecular indicators of efficacy that will clarify what cancer types might be most susceptible to this approach. We also plan to exploit the therapeutic potential of multivalent ligands beyond HER3, as the induced receptor degradation observed in our recent work may represent a broad mechanism of anti-neoplastic activity that is potentially useful against a myriad of targets. Ultimately, engineered multivalent ligands offer a versatile alternative to antibody therapeutics with the potential for improved clinical cancer therapy.
I’ll be presenting my research on Monday May 16 from 12:45 pm–1:45 pm (poster M1005) and via podium talk on Wednesday May 18 from 12:45 pm–1:05 pm in Back Bay Ballroom C during the 2016 AAPS National Biotechnology Conference. Stop by to learn more!