We developed a functional lineage tracing tool termed CaTCH (CRISPRa Tracing of Clones in Heterogeneous cell populations). CaTCH combines precise clonal tracing of millions of cells with the ability to retrospectively isolate founding clones alive prior to and during selection, allowing functional experiments. Using CaTCH, we captured rare clones representing as little as 0.001% of a population and investigated the emergence of resistance to targeted melanoma therapy in vivo .

Ovarian cancer (OC) is the deadliest gynecological cancer, and novel therapeutic options are crucial to improve overall survival. Here we provide evidence that impairment of oxidative phosphorylation (OXPHOS) can help control OC progression, and this benefit correlates with expression of the two mitochondrial master regulators PGC-1α and PGC-1β.In orthotopic patient-derived ovarian cancer xenografts (OC-PDX), concomitant high expression of

Poly (ADP-ribose) polymerase inhibitors (PARPi) have changed the management of ovarian cancer patients and their effectiveness has been demonstrated especially in homologous recombination repair-deficient tumors. These first-generation drugs target PARP1, but also PARP2 and other family members potentially responsible for adverse effects that limit their therapeutic potential and restrict their use in combination with chemotherapeutic agents. We investigated patient-derived ovarian cancer xenografts (OC-PDXs) to assess whether malignant progression could be impaired by a novel inhibitor selective for PARP1 (AZD5305) and to assess the potential of its combination with carboplatin (CPT), the standard-of-care for ovarian cancer patients. In BRCA-mutated OC-PDXs, AZD5305 achieved greater tumor regressions and longer duration of response as well as a superior impairment of visceral metastasis and improved survival benefit compared to the first-generation dual PARP1/2 inhibitors. The combination of AZD5305 plus CPT was more efficacious than single-agents. Subcutaneously growing tumors experienced regression that persisted after therapy stopped. Combination efficacy was greater against tumors that did not respond well to platinum, even at a dose at which AZD5305 monotherapy was ineffective. The combination therapy impaired metastatic dissemination and significantly prolonged the lifespan of mice bearing OC-PDXs in their abdomen. This combination benefit was evident even when CPT was used at suboptimal doses, and was superior to full dose platinum treatment. These pre-clinical studies demonstrate that the PARP1-selective inhibitor AZD5305, retains and improves the therapeutic benefit of the first-generation PARPi, providing an opportunity to maximize benefits for this class of anti-cancer agents.

Supplementary Data from PGC1α/β Expression Predicts Therapeutic Response to Oxidative Phosphorylation Inhibition in Ovarian Cancer