THE CRITICAL NEED

Embracing the complexity of cancer

Cancer is complex, arising through the accumulation of multiple genetic events, in patterns unique to subgroups of tumors. The effects of these oncogenic alterations are to 1) inactivate protective genes (loss of tumor suppressors), 2) create multiple driver oncogenes and 3) help cancer avoid destruction by immune cells.

Despite the well-established patterns of complexity in cancer, current genetically targeted therapies address only a fraction of known oncogenic events and are used primarily as single agents. The first generation of targeted therapies yielded advances for selected patients, shrinking, but rarely eliminating tumors. In addition, while recent immuno-oncology drugs show promise in some tumor types, and a fortunate few have long-term complete responses, the majority of patients do not benefit, regardless of tumor type.

OPPORTUNITIES FOR DISCOVERY

Addressing tumor suppressor gene loss

A universal step in cancer progression is the loss of function in tumor suppressor genes - genes that normally protect against tumor development. We are focused on discovering novel targets using synthetic lethality, where the cancer-causing alteration in a tumor suppressor gene creates a vulnerability that leads to tumor cell killing when targeting a second gene, but only in that genetic context, leading to less toxic, more effective treatments.

OPPORTUNITIES FOR DISCOVERY

Targeting multiple oncogenic drivers

As cancer is caused by multiple genetic changes, it follows that combination therapies are needed for cures. This is well-established in testicular cancer, Hodgkin lymphoma, childhood leukemias, and others cancers that are curable with combination, but not single agent chemotherapy. Most druggable oncogenes have been identified by their genetic alterations (eg. amplified HER2, mutated BRAF) and drugs against these targets are active as single agents, but don’t drive cures. Many additional targets likely exist, but represent context dependent effects and lack genetic mutations (eg. estrogen blockade and CDK4/6 inhibition in ER+ breast cancer). Our approach is powered to identify these critical drug targets allowing us to define the next generation of highly effective, combination therapies for cancer.

OPPORTUNITIES FOR DISCOVERY

Reversing immune evasion

We are just starting to identify the genetic alterations responsible for programming cancer cells to avoid immune destruction. Our platform is powered to uncover those targets that reverse immune evasion, allowing cancer cells to be recognized and removed by the immune system. This approach complements current immune cell-directed cancer therapies and will further enhance the benefit of this important therapeutic class.

A POWERFUL APPROACH

Accelerating discovery by putting patient selection first

We use deep DNA sequencing and CRISPR-based screening to identify targets for specific subgroups of cancer patients. Our goal is to leverage the principles of synthetic lethality to find the weaknesses in cancer cells created by genetic complexity and use them to provide a roadmap to cures.

Our discovery engine

Our discovery efforts begin and end with patients. We invert the traditional discovery paradigm by putting patient selection before target identification to provide the right medicines to the right patient to improve speed and success in drug development. Essential to this effort is depth of understanding of the genetic subtypes of cancer and the drug combinations uniquely relevant to each subtype. As we advance into the clinic, our trials will enroll the patients most likely to benefit from our new treatments, enabling speed, success and impact for patients.