In human cells, damage to DNA is a daily occurrence arising from metabolic activities and environmental factors. Thousands of DNA damage events routinely occur every day in each cell. If left unchecked and unrepaired, these impair the structural integrity of DNA molecules and mutate the genetic information necessary for cells to function normally. Cell survival is therefore dependent on a series of processes that takes place following DNA damage, collectively called the DNA damage response (DDR).
DDR orchestrates a complex network of cellular processes that can either detect and repair damage to DNA or induce irreversible growth arrest and cell death if the damage is too severe. Most cancer cells have defective DDR, promoting a state where mutations accumulate, and cell growth is uncontrolled.
Many standard-of-care oncology treatments, including chemotherapy and radiotherapy, directly damage DNA with the goal of turning on DDR mechanisms to kill cancer cells. Because these treatments also damage the DNA of normal cells and do not activate DDR mechanisms that only cancer cells use, they have an inevitable impact on healthy tissues. This results in side effects and limited efficacy – a small therapeutic window.
Cancer-specific, DDR-targeted therapies offer a more powerful treatment paradigm.
Insights into how pre-cancerous cells alter DDR pathways to grow, form tumors and escape the body’s immune defenses have opened a door to a new generation of effective anti-cancer drugs. Novel molecules that are designed to exploit cancer-specific alterations in DDR pathways also provide a new avenue to address tumors that are refractory or have become resistant to existing treatment. By utilizing highly targeted and safe compounds, alone and in combination with other cancer treatments, DDR-directed oncology approaches can achieve a new level of therapeutic impact.
Breakpoint Therapeutics is leveraging this new knowledge. We deploy our proprietary insights combined with a depth of drug development expertise to advance a pipeline of next generation DDR therapies.
Our drug candidates are designed to:
Achieve Synthetic Lethality
Synthetic lethality refers to a genetic interaction in which two single genetic defects are each individually tolerable for cell survival, but the combination of these defects is lethal to the cell.
Some of the genetic alterations that cancer cells acquire to support their growth create vulnerabilities that can be exploited through this concept. For example, alterations in a specific DNA repair pathway will cause those cancer cells to become dependent on another repair option to survive. This is a synthetic lethal dependency. Where it involves a “back-up” pathway – used by cancer but not essential for healthy cells – there is opportunity to inhibit this with a drug to selectively eliminate diseased cells with little or no impact on normal tissue. Such a drug engenders the same effect as a second genetic deficiency and thereby achieves synthetic lethality. By understanding the DDR and analyzing a tumor’s genetic code for alterations that lead to dependencies, patients can be matched to the right targeted drugs, resulting in more effective treatment.
Overcome Therapy Resistance
Cancer cells can exploit DNA repair pathways to evade standard-of-care treatments and targeted agents. Often this is achieved by overexpressing repair factors, resulting in low treatment efficacy.
The overexpression of certain repair proteins in cancer cells correlates with resistance to chemotherapeutic agents and ineffective radiotherapy. Moreover, these DNA repair proteins can be directly responsible for new mutations that lead to resistant tumor cells. Inhibiting such mediators of cancer DDR provides a tool to sensitize cancers to specific treatments and reduce the development of drug resistance, thereby enabling improved outcomes for patients.
Increase the Therapeutic Impact of Validated Treatments
PARP inhibitors, the first DDR-targeted drugs to achieve clinical success, have validated the concept of inhibiting DNA repair in oncology. Nevertheless, PARP inhibitors currently help only a small fraction of cancer patients.
Breakpoint’s DDR-focused therapeutic programs target different pathways, which, either alone or in combination with other targeted drugs like PARP inhibitors, could expand the breadth of cancer types and therefore numbers of patients that respond to these innovative treatments. Based on their highly specific mode of action, Breakpoint’s DDR inhibitors may also boost the efficacy of a range of existing therapies, such as chemotherapy and immune checkpoint inhibitors, when administered together in modern treatment regimens.