The Science | THE NUCLEOTIDE EXCISION REPAIR PATHWAY
Cancer is characterized by uncontrolled proliferation of cells. Treating cancer involves stopping the cell division or inducing cell death in an attempt to shrink and eradicate a tumor. Cisplatin is active in killing cancer cells because it damages DNA. Our approach builds on this crucial activity in that our SMIs block the cells response to DNA damage giving cisplatin more time to work at eradicating the tumor. Cellular proteins responsible for making cisplatin less effective work by repairing damage to DNA and are our top three top targets (RPA, XPA, XPF- ERCC1). Targeting DNA repair has gained considerable traction with the clinical trials of PARP- inhibitors. While as single agents they are showing some activity, combination studies have met with mixed results opening up the playing field for novel targets in the DNA repair arena. Our NER inhibitors have the advantage over PARP inhibitors because they directly target the pathway that limits cisplatin efficacy and thus they were designed to work in combination with current therapeutic agents like cisplatin.
Our pipeline of SMIs is based on the discoveries from Chief Scientific Officer Dr. John Turchi's lab at the Indiana University School of Medicine. His work in studying the Nucleotide Excision Repair pathway has led to dramatic advances in our understanding of cancer over the past decade. Through his research, we have identified several small molecules that inhibit DNA binding activity of NER recognition proteins. These SMIs will introduce the first molecular therapies targeting a protein/DNA interaction in essence; this is the fist step in a new generation of drugs to fight cancer. As many oncologists believe, this is the future of cancer therapy.
The Clinical Reality of Common Cancers
- In 2013, 22% of new cases and 25% of cancer deaths (over 200,000) came from 3 cancers, lung, breast and ovarian.
- Urgent unmet need for new therapies to combat these difficult to treat highly prevalent cancers.
- Despite the advent of targeted therapies which focus on tumor growth pathways, single agent treatment is rare, and combination therapy based on differential toxicity profiles are often ineffective and costly to get to the clinic.
Nearly half of all individuals diagnosed with cancer will receive a platinum-based therapeutic agent as part of their treatment regimen.
- The effectiveness of these agents varies from limited efficacy in lung cancer to curative in the case of testicular germ cell tumors.
- NĒRx BioSciences is developing novel therapeutics designed to work with and enhance the activity of platinum-based agents.
Rationale: biology based targeted therapies designed to work in combination with the most prescribed cancer therapeutic, Cisplatin.
- Cisplatin causes DNA damage
- Cisplatin-DNA damage is repaired by the NER pathway (our namesake).
- Repair of cisplatin-DNA damage is detrimental to efficacy.
- Clinical response to cisplatin is a function of DNA repair.
- Sensitive cancers have reduced repair capacity (testicular).
- Resistant cancers have intrinsically or acquired increased repair capacity (lung and ovarian).
Platform: Target repair of Pt-DNA damage via disruption of NER pathway
Clinical validation of NER targets
- XPA expression inversely correlates with relapse free survival in breast cancer and progression free survival in ovarian cancer and overall survival in lung cancer.