Biology subjects

Dela Cruz, F. S.

Publications and source records attributed to Dela Cruz, F. S..

3 recordsLinked to original sources

bioRxiv2023

Overcoming clinical resistance to EZH2 inhibition using rational epigenetic combination therapy

Essential epigenetic dependencies have become evident in many cancers. Based on the functional antagonism between BAF/SWI/SNF and PRC2 in SMARCB1-deficient sarcomas, we and colleagues recently completed the clinical trial of the EZH2 inhibitor tazemetostat. However, the principles of tumor response to epigenetic therapy in general, and tazemetostat in particular, remain unknown. Using functional genomics of patient tumors and diverse experimental models, we sought to define molecular mechanisms of tazemetostat resistance in SMARCB1-deficient sarcomas and rhabdoid tumors. We found distinct classes of acquired mutations that converge on the RB1/E2F axis and decouple EZH2-dependent differentiation and cell cycle control. This allows tumor cells to escape tazemetostat-induced G1 arrest despite EZH2 inhibition, and suggests a general mechanism for effective EZH2 therapy. This also enables us to develop combination strategies to circumvent tazemetostat resistance using cell cycle bypass targeting via AURKB, and synthetic lethal targeting of PGBD5-dependent DNA damage repair via ATR. This reveals prospective biomarkers for therapy stratification, including PRICKLE1 associated with tazemetostat resistance. In all, this work offers a paradigm for rational epigenetic combination therapy suitable for immediate translation to clinical trials for epithelioid sarcomas, rhabdoid tumors, and other epigenetically dysregulated cancers. SignificanceGenomic studies of patient epithelioid sarcomas, rhabdoid tumors, and their cell lines identify mutations converging on a common pathway that is essential for response to EZH2 inhibition. Resistance mutations decouple drug-induced differentiation from cell cycle control. We identify complementary epigenetic combination strategies to overcome resistance and improve durability of response, supporting their investigation in clinical trials.

cancer biology↗

bioRxiv2021

Pre-clinical validation of an RNA-based precision oncology platform for patient-therapy alignment in a diverse set of human malignancies resistant to standard treatments

Predicting tumor sensitivity to antineoplastics remains an elusive challenge, with no methods demonstrating predictive power. Joint analysis of tumors--from patients with distinct malignancies who had progressed on multiple lines of therapy--and drug perturbation transcriptional profiles predicted sensitivity to 28 of 350 drugs, 26 of which (93%) were confirmed in low-passage, patient-derived xenograft (PDX) models. Drugs were prioritized based on their ability to either invert the activity of individual Master Regulator proteins, with available high-affinity inhibitors, or of the modules they comprise (Tumor-Checkpoints), based on de novo mechanism of action analysis. Of 138 PDX mice enrolled in 16 single and 18 multi-protein treatment arms, a disease control rate (DCR) of 68% and 91 %, and an objective response rate (ORR) of 12% and 17%, were achieved respectively, compared to 6% and 0% in the negative controls arm, with multi-protein drugs achieving significantly more durable responses. Thus, these approaches may effectively complement and expand current precision oncology approaches, as also illustrated by a case study.

systems biology↗

bioRxiv2021

Identification and validation of a non-genetically encoded vulnerability to XPO1 inhibition in malignant rhabdoid tumors - expanding patient-driven discovery beyond the Nof1.

Malignant rhabdoid tumors (MRTs) are rare, aggressive pediatric solid tumors, characterized by a 22q11 deletion that inactivates the SMARCB1 gene. Outcomes remain poor despite multimodality treatment. MRTs are among the most genomically stable cancers and lack therapeutically targetable genetic mutations. We utilized metaVIPER, an extension of the Virtual Inference of Protein-activity by Enriched Regulon (VIPER) algorithm, to computationally infer activated druggable proteins in the tumor of an eight month old patient and then expanded the analysis to TCGA and TARGET cohorts. In vitro studies were performed on a panel of MRT and atypical teratoid/rhabdoid tumor cell lines. Two patient-derived xenograft (PDX) mouse models of MRT were used for in vivo efficacy studies. MetaVIPER analysis from the patients tumor identified significantly high inferred activity of nuclear export protein Exportin-1 (XPO1). Expanded metaVIPER analysis of TCGA and TARGET cohorts revealed consistent elevations in XPO1 inferred activity in MRTs compared to other cancer types. All MRT cell lines demonstrated baseline activation of XPO1. MRT cell lines demonstrated in vitro sensitivity to the XPO1 inhibitor, selinexor which led to cell cycle arrest and induction of apoptosis. Targeted inhibition of XPO1 in patient-derived xenograft models of MRT using selinexor resulted in abrogation of tumor growth. Selinexor demonstrates efficacy in preclinical models of MRT. These results support investigation of selinexor in a phase II study in children with MRT and illustrate the importance of an N-of-1 approach in driving discovery beyond the single patient. Statement of Translational RelevanceWe describe the patient-driven discovery of XPO1 activation as a non-genetically encoded vulnerability in MRTs. The application of metaVIPER analysis to tumors lacking actionable oncogenic alterations represents a novel approach for identifying potential therapeutic targets and biomarkers of response. Our preclinical validation of selinexor confirms XPO1 inhibition as a promising therapeutic strategy for the treatment of MRT.

cancer biology↗