Sensitizing thermochemotherapy with a PARP1-inhibitor

Cis-diamminedichloroplatinum(II) (cisplatin, cDDP) is an effective chemotherapeutic agent that induces DNA double strand breaks (DSBs), primarily in replicating cells. Generally, such DSBs can be repaired by the classical or backup non-homologous end joining (c-NHEJ/b-NHEJ) or homologous recombination (HR). Therefore, inhibiting these pathways in cancer cells should enhance the efficiency of cDDP treatments. Indeed, inhibition of HR by hyperthermia (HT) sensitizes cancer cells to cDDP and in the Netherlands this combination is a standard treatment option for recurrent cervical cancer after previous radiotherapy. Additionally, cDDP has been demonstrated to disrupt c-NHEJ, which likely further increases the treatment efficacy. However, if one of these pathways is blocked, DSB repair functions can be sustained by the Poly-(ADP-ribose)-polymerase1 (PARP1)-dependent b-NHEJ. Therefore, disabling b-NHEJ should, in principle, further inhibit the repair of cDDP-induced DNA lesions and enhance the toxicity of thermochemotherapy. To explore this hypothesis, we treated a panel of cancer cell lines with HT, cDDP and a PARP1-i and measured various end-point relevant in cancer treatment. Our results demonstrate that PARP1-i does not considerably increase the efficacy of HT combined with standard, commonly used cDDP concentrations. However, in the presence of a PARP1-i, ten-fold lower concentration of cDDP can be used to induce similar cytotoxic effects. PARP1 inhibition may thus permit a substantial lowering of cDDP concentrations without diminishing treatment efficacy, potentially reducing systemic side effects

Enhancing synthetic lethality of PARP-inhibitor and cisplatin in BRCA-proficient tumour cells with hyperthermia

Background: Poly-(ADP-ribose)-polymerase1 (PARP1) is involved in repair of DNA single strand breaks. PARP1-inhibitors (PARP1-i) cause an accumulation of DNA double strand breaks, which are generally repaired by homologous recombination (HR). Therefore, cancer cells harboring HR deficiencies are exceptionally sensitive to PARP1-i. For patients with HR-proficient tumors, HR can be temporarily inhibited by hyperthermia, thereby inducing synthetic lethal conditions in every tumor type. Since cisplatin is successfully used combined with hyperthermia (thermochemotherapy), we investigated the effectiveness of combining PARP1-i with thermochemotherapy. Results: The in vitro data demonstrate a decreased in cell survival after addition of PARP1-i to thermochemotherapy, which can be explained by increased DNA damage induction and less DSB repair. These in vitro findings are in line with in vivo model, in which a decreased tumor growth is observed upon addition of PARP1-i. Materials and Methods: Survival of three HR-proficient cell lines after cisplatin, hyperthermia and/or PARP1-i was studied. Cell cycle analyses, quantification of γ-H2AX foci and apoptotic assays were performed to understand these survival data. The effects of treatments were further evaluated by monitoring tumor responses in an in vivo rat model. Conclusions: Our results in HR-proficient cell lines suggest that PARP1-i combined with thermochemotherapy can be a promising clinical approach for all tumors independent of HR status

Keeping your best options open with AI-based treatment planning in prostate and cervix brachytherapy

PURPOSE: Without a clear definition of an optimal treatment plan, no optimization model can be perfect. Therefore, instead of automatically finding a single “optimal” plan, finding multiple, yet different near-optimal plans, can be an insightful approach to support radiation oncologists in finding the plan they are looking for. METHODS AND MATERIALS: BRIGHT is a flexible AI-based optimization method for brachytherapy treatment planning that has already been shown capable of finding high-quality plans that trade-off target volume coverage and healthy tissue sparing. We leverage the flexibility of BRIGHT to find plans with similar dose-volume criteria, yet different dose distributions. We further describe extensions that facilitate fast plan adaptation should planning aims need to be adjusted, and straightforwardly allow incorporating hospital-specific aims besides standard protocols. RESULTS: Results are obtained for prostate (n = 12) and cervix brachytherapy (n = 36). We demonstrate the possible differences in dose distribution for optimized plans with equal dose-volume criteria. We furthermore demonstrate that adding hospital-specific aims enables adhering to hospital-specific practice while still being able to automatically create cervix plans that more often satisfy the EMBRACE-II protocol than clinical practice. Finally, we illustrate the feasibility of fast plan adaptation. CONCLUSIONS: Methods such as BRIGHT enable new ways to construct high-quality treatment plans for brachytherapy while offering new insights by making explicit the options one has. In particular, it becomes possible to present to radiation oncologists a manageable set of alternative plans that, from an optimization perspective are equally good, yet differ in terms of coverage-sparing trade-offs and shape of the dose distribution