Recognition of MUC1’s overexpression in cancers is well established. But Genus’ unique approach is new, and offers the potential to significantly advance the treatment of cancer.
The science: basic and applied
The normal physiologic function of MUC1 (Mucin1) is designed to provide a protective barrier for the outer surface of epithelial cells, the cells which form layers both outside and inside organs and body cavities. This barrier prevents caustic elements — toxins, infections, free radicals, acids and other forms of cell stress — from having direct contact with the epithelial cell.
MUC1 proteins are commonly described as hair-like filaments extending on the apical exterior of an epithelial cell. Under stress, the exterior portion of the MUC1 protein breaks away. This phenomenon is known as cleavage, and the resulting protein fragments as shed ectodomain.
MUC1: the Intracellular Domain
The MUC1 protein also extends across the cell membrane into the cell itself. This intracellular portion plays a key role in the signaling that increases cell growth activity and protects against cell death.
Tumors have exploited this second role by overexpressing MUC1, which dramatically increases cell growth conditions and blocks the cell death pathways used by common anti-cancer drugs. In an epithelial cell exhibiting this phenomenon, MUC1 is no longer confined to the apical side of the cell. MUC1 proteins — along with the growth factor receptors which are normally restricted to the basal side of a healthy cell — are overexpressed and radiate from all sides.
MUC1 and Cancer
In brief, MUC1 receptors are key in facilitating the growth of cancer. MUC1:
- Induces unrestricted growth;
- Blocks death pathways; and
- Contributes to metastases.
Common Pharmaceutical Approaches
Other development programs are focused on suppressing tumor growth by directing antibodies or vaccines at the extracellular portion of MUC1. Success to date has been underwhelming using this approach, and tumor growth tends to restart after a short period of suppression. Since the target of these therapies is the ectodomain which cleaves and is shed from the cell, it’s not surprising that affected MUC1 proteins — still intact in the cytoplasm — soon regenerate and continue the process of tumor cell growth.
Genus Research and Approach
Based on research conducted at Dana-Farber Cancer Institute (DFCI), Harvard Medical School, Genus scientists have centered their efforts on designing peptides and small molecules to compete for key binding sites.
As a result, our scientists were able to successfully design and synthesize peptides which block the ability of MUC1 to oligomerize. When studied for activity in multiple cancer cell lines, treatment of cells with MUC1-targeting peptides was associated with growth arrest and tumor cell death. By contrast, no effect was observed in normal cells. Furthermore, treatment of MUC1 positive cancer xenografts in mice was associated with extensive tumor cell death and loss of tumorgenicity, resulting in significant and prolonged regression of tumor growth.
The mechanism of action for the new peptides has been identified, and in vitro and in vivo studies have confirmed that the peptides have significant and prolonged antitumor activity in MUC1 expressing tumors. We have tested the lead MUC1 inhibitors in multiple animal models such as hormone-dependent breast carcinomas, triple-negative breast cancer, and refractory prostrate cancer; all animals experienced complete responses and remained tumor free 125 days post treatment. In addition, the drug appeared to be well tolerated at the three doses used in our studies. Additional in vivo studies are currently ongoing in non-small cell lung, pancreatic, ovarian and colon cancers, and liquid leukemias.
Genus has developed a synthetic version of our lead drug candidate, which has significantly increased the stability when compared to native peptides. Genus has completed initial pharmacology and toxicology studies which show that the peptide has pharmaceutical characteristics that will allow it to be a viable drug candidate. These studies were used to select a drug regimen for our Phase I clinical trial which is currently enrolling patients at multiple sites across the U.S.