Acworth Pharmaceuticals is a Seed stage company pioneering the discovery and development of first-in-class regulatory therapeutics that kill cancer by restoring normal cellular function based on the novel biology of DKK3.
Abnormal cell growth is a universal feature of cancer. However, the identification of a common core of cellular defects responsible for cancer remains elusive. Disrupted cell signaling pathways are common targets for therapeutic intervention in cancer but have often met with marginal success. Disqualifying off-target effects, and unwanted or toxic side-effects are commonly encountered in clinical trials.
Acworth is using its deep understanding of DKK3 biology to discover and develop direct-acting regulators that restore normal recycling function to signaling pathways disrupted in cancer. In many cancers, the ability to return dysregulated signaling molecules to a normal state in the cell is compromised by the loss of key factors that initiate the recycling process.
Abnormal Wnt, NFkB and mTOR signaling are frequent actors in the neoplastic process. For example β-catenin is one such regulatory signal of the Wnt pathway whose function is disrupted by oncogenic mutations in colorectal, liver, breast, prostate, ovarian, glioblastoma, lung, pancreatic and other cancers. Impaired β-catenin processing leads to increased signaling that directly causes abnormal cell growth and hyperproliferation and limits the value of newer treatments like immunotherapies. Our therapeutic regulators restore the normal recycling function to the disrupted signaling pathway(s), interrupt the signaling cascade, arrest cancer cell proliferation, and initiate cancer cell death.
A platform to restore normal signaling pathway function.
Acworth’s MEND (Miniproteins that reEstablish Normal Distribution) platform is based on co-founder Jack Leonard’s original discovery that the dkk3 gene encodes a second vital modulatory protein, DKK3b, that restores normal function to defective cell signaling pathways in disease.
The two common drug modalities in use today are small molecules and protein biologics. The relatively large size of biologics and their notorious inability to cross the cell membrane limit their utility for intracellular druggable targets. Acworth’s approach utilizes native functional domains and rationale design to engineer therapeutic miniproteins capable of engaging and defeating intracellular disease targets. Acworth exploits the natural cellular recycling machinery of key "transfer stations" in cells to restore normal function.
What Acworth's Targeted Charperone Mimetics (TCM) Do
TCMs are cell permeable miniproteins that combine the power of biologics with the cell-entry ability of small molecules. Because many of the targeted signaling pathways contribute to creating “cold” cancer phenotypes, correcting these defects partnered with immuno-oncology therapeutics offers a real opportunity to expand the treatable tumor landscape. This approach revolutionizes the global delivery of biological modulators and offers new therapeutic approaches to refractory disease.
Acworth’s insight into how cells regulate key signaling molecules is founded on the discovery of a universal regulated recycling/redistribution machinery in cells. Vital regulatory processes control cell signaling pathways in normal cells by a combination of signal molecule degradation and signal molecule redistribution. When these modulating functions are disrupted due to the loss of critical regulatory factors, intracellular control of the signaling molecule is lost resulting in uncontrolled cell responses. In the case of many cancers, mutations in one or more signaling pathway components causes excessive levels of key signal molecules that drive cell proliferation.
Patient derived, cisplatin resistant, ovarian cancer cells after 36 hours in culture.
Our novel miniprotein drug candidates readily enter and work inside the cell. Once inside, Acworth’s therapeutics restore the recycling function of signaling pathway control at the intersection of recycling and degradation. TrCP is one E3 Ubiquitin ligase that occupies this decision point making the choice of destruction through ubiquitination, or recycling to the cell periphery.
Our MEND platform exploits this essential recycling function of TrCP to redirect signaling molecules away from the nucleus and the proteosome. Because only cancer cells lack these vital recycling regulators, our technology resurrects normal cellular control in mutated cells without affecting normal tissues. In addition, this return to normal of the sorting process in cancer cells avoids compensatory changes in protein turnover.
We have all been affected by cancer directly or indirectly in our own lives through the loss of family, friends, and co-workers; and we know first-hand the urgent need for new, effective treatments for cancer patients and those with other intractable diseases. We seek others who share our vision for making patients lives better, who will work tirelessly, and are devoted to succeeding in this effort.
Prior to establishing Acworth, he served most recently as CEO at Blue Sky BioServices, through its combination with LakePharma, and CBO at Xcellerex before its acquisition by GE. Ted has prior cancer experience as VP, Business Development at Point Therapeutics, and at Beyond Genomics (BG Medicine), and Business Development at Eli Lilly and Company.
DAVID RYAN, MD
Chief of Hematology/Oncology, Massachusetts General Hospital (MGH) and a Professor of Medicine, Harvard Medical School. The principal focus of his clinical research is the design and implementation of Phase I and II trials in gastrointestinal malignancies.
GILES WHELAN, MD
Chief, Division of Surgical Oncology and Endocrine Surgery, UMass Memorial Hospital, and Professor, University of Massachusetts Medical School.
Acworth benefits from the experience and support of a growing group of advisors.
CLARY CLISH, PHD
Senior Director of the Metabolomics Platform and Institute Scientist at the Broad Institute of MIT and Harvard.
SCOT WOLFE, PHD
Professor of Molecular, Cell and Cancer Biology at UMass Medical School.
Travis is a professional investor and was formerly Managing Partner of Monitor Clipper Partners, a private equity firm that invested over $2 billion globally. He is also a personal angel investor, with over twenty current investments, primarily in the Boston area. He sits on the board of numerous private companies.
We are driven to succeed by the potential of our technology to treat currently untreatable cancers.
Almost 1.9 million new cancer cases are expected to be diagnosed in 2021 in the United States alone.
Globally, there will be nearly 20 million cases.
Approximately 608,570 Americans are expected to die of cancer in 2021, which translates to about 1,670 deaths per day.
Cancer is the second most common cause of death in the US, exceeded only by heart disease.
In cancers like pancreatic, colotrectal, ovarian, melanoma, where β-catenin is a key driver, we will have an impact and provide fuller lives to patients.
Acworth has a novel platform and unique understanding of how to apply its technologies in cancer.