Schucht, P. | Search bioRxiv

bioRxiv2023

Systematic microRNA screening identifies miR-19b as regulator of temozolomide response through targeting PP2A serine-threonine phosphatase in glioblastoma

Despite the standard of care, glioblastoma IDH wildtype (GBM) inevitably recurs, underscoring the need to develop new treatment strategies. To address the role of microRNAs in temozolomide (TMZ) response, we performed functional microRNA screens and consistently identified miR-19b. Our study reveals a novel axis between miR-19b and PPP2R5E subunit of serine/threonine protein phosphatase PP2A and establishes a so far unappreciated contribution of miR-19b in TMZ resistance of GBM. Specifically, our results demonstrate that attenuation of miR-19b in GBM cell lines and glioblastoma stem cells (GSCs) induces DNA damage, which further enhances the cytotoxic effects of TMZ treatment. We confirmed TMZ resistance induced by knocking down PPP2R5E in orthotopic mouse xenografts of GSCs. Furthermore, our results indicate that treating cells with the PP2A-activating drug FTY720 or knocking down endogenous PP2A-inhibiting proteins potentiates the cytotoxic effects of TMZ. MiR-19b attenuation or PPP2R5E activation could potentially be exploited in adjuvant therapy of GBM patients.

cancer biology↗

bioRxiv2019

Computational design of improved standardized chemotherapy protocols for grade II oligodendrogliomas

The use of mathematical models for personalization of cancer therapies and raising hypothesis of potential clinical impact is an emerging topic in the interface between mathematics and oncology. Here we put forward a mathematical model describing the response of low-grade (WHO grade II) oligodendrogliomas (LGO) to temozolomide (TMZ). The model described the longitudinal volumetric dynamics of tumor response to TMZ of a cohort of 11 LGO patients treated with TMZ. After finding patient-specific parameters, different therapeutical strategies were tried computationally on the in-silico twins of those patients. Chemotherapy schedules with larger-than-standard rest periods between consecutive cycles had either the same or better long-term efficacy than the standard 28-day cycles. The results were confirmed in a large virtual clinical trial including 2000 patients. These long-cycle schemes would also have reduced toxicity and defer the appearance of resistances.\n\nOn the basis of those results, a combination scheme consisting of five induction TMZ cycles given monthly plus 12 maintenance cycles given every three months was found to provide substantial survival benefits for the in-silico twins of the 11 LGO patients (median 5.69 years, range: 0.67 to 68.45 years) and in a large virtual trial including 2000 patients. This scheme could be useful for defining a standardized TMZ treatment for LGO patients with survival benefits.\n\nAuthor summaryA mathematical model described the longitudinal volumetric growth data of grade II oligodendrogliomas patients and their response to temozolomide. The model was used to explore alternative therapeutical protocols for the in-silico twins of the patients and in virtual clinical trials. The simulations show that enlarging the time interval between chemotherapy cycles would maintain the therapeutical efficacy, while limiting toxicity and defering the development of resistances. This may allow for improved drug-exposure by administering a larger number of cycles for longer treatment periods. A scheme based on this idea consisting of an induction phase (5 consecutive cycles, 1 per month) and a maintenance phase (12 cycles given in three-months intervals) led to substantial survival benefits in-silico.

cancer biology↗