- |||||||||| Undisclosed YAP/TAZ-TEAD inhibitor / Hanmi
Predicting cancer cell response to TEAD auto-palmitoylation inhibitor using bulk RNA-seq data and a random-forest based algorithm (Section 32; Poster Board #19) - Mar 14, 2023 - Abstract #AACR2023AACR_6816; These TEAD inhibitors disrupt YAP/TAZ-TEAD protein interaction, suppress TEAD transcriptional activity, and selectively block proliferation of NF2-deficient mesothelioma in vitro and inhibit NF2 mutant xenograft tumor growth in vivo...Then from our screen of 50 patient-derived Chinese liver cancer (CLC) cell models (Qiu et al, 2019, Cancer Cell), both as single agent and in combination with mTOR inhibitor everolimus, we found that TEAD inhibitors (TEADi) were efficacious in several of these liver cancer models...Having established efficacy of predictions on both in vitro datasets, we re-trained the classifier using both CCLE and CLC datasets as input to achieve maximum predictive performance, and we predicted, post-hoc, response status of 99 responders out of 2056 patient-derived xenograft models. The algorithm showed early promise by retrospectively classifying a model with in vivo efficacy as the most likely to respond.
- |||||||||| ARV-471 / Arvinas, Pfizer
Enhanced efficacy of ARV-471, a novel PROTAC (Section 29; Poster Board #14) - Mar 14, 2023 - Abstract #AACR2023AACR_4848; ARV-471 also displayed greater anti-tumor activity in combination with abemaciclib, ribociclib or inavolisib than that observed with fulvestrant in combination with these agents. Taken together, these data suggest the potential utility of ARV-471 as a combination partner for clinically relevant targeted agents for treatment of early and late-stage ER+ disease.
- |||||||||| dordaviprone (ONC201) / Chimerix
Acquired sensitivity to ONC201/TIC10 in ER+ breast cancer progressing on the mTOR inhibitor everolimus (Section 14; Poster Board #14) - Mar 14, 2023 - Abstract #AACR2023AACR_2491; Combining patient derived data with resistant cell line driven experiments, our study provides validated findings in various settings strengthening the potential for clinical applications of ONC201/TIC10. We propose that ONC201/TIC10 and modulation of mitochondrial function is effective in drug resistant cancer cells and can enhance the anti-tumor activity of standard of care therapy in progressing patients.
- |||||||||| SMIP34 / Evestra, UT Health Science Center
The role of PELP1 inhibitor SMIP34 in the treatment of endometrial cancer (Section 16; Poster Board #4) - Mar 14, 2023 - Abstract #AACR2023AACR_2451; Response rates and progression free survival are still low for recurrent ECa treatments such as hormone therapy, chemotherapy, and targeted therapies like Bevacizumab and Everolimus. Collectively, our results suggest that SMIP34 inhibits ECa growth in vitro, in vivo, and ex vivo and combination of SMIP34 with mTOR inhibitor represents a novel therapeutic strategy for ECa.
- |||||||||| RMC-5552 / Revolution Medicines, sapanisertib (CB-228) / Calithera
Bi-steric mTORC1-selective inhibitors activate 4EBP1, suppress MYC, restore anti-tumor immunity, and cooperate with immune checkpoint inhibition to elicit tumor regression (Section 35; Poster Board #7) - Mar 14, 2023 - Abstract #AACR2023AACR_2072; P1 However, to date, existing mTOR pathway inhibitors such as everolimus or sapanisertib fail to sufficiently decrease MYC protein levels in vivo because of incomplete inhibition of p4EBP1 or toxicities that limit the activity, respectively...RMC-5552, a representative of the bi-steric class of selective mTORC1 inhibitor, is currently in Phase 1 clinical trials (NCT04774952)...Overall, we provide proof-of-principle that selective mTORC1 pharmacological inhibition can effectively target MYC-driven cancers by reducing MYC levels, combine with immune checkpoint inhibition, re-establish anti-tumor immunity, and induce sustained tumor regression in the preclinical setting. These preclinical findings provide a rationale for clinical trials with selective mTORC1 inhibitors in patients with MYC-driven cancers and moreover, support clinical testing of combination with immune checkpoint inhibition.
- |||||||||| Piqray (alpelisib) / Novartis
Journal: Discovering Synergistic Compounds with BYL-719 in PI3K Overactivated Basal-like PDXs. (Pubmed Central) - Mar 11, 2023 BYL-719-based, synergistic two-drug combinations were identified with 20 different compounds, including everolimus, afatinib, and dronedarone, which were also found to be effective at minimizing tumor growth. These data support the use of these drug combinations towards cancers with activating PIK3CA mutations/gene amplifications or PTEN deficient/PI3K overactive pathways.
- |||||||||| Piqray (alpelisib) / Novartis
Journal: PIK3CA copy number gain and inhibitors of the PI3K/AKT/mTOR pathway in triple-negative breast cancer. (Pubmed Central) - Mar 3, 2023 Hence, we discuss the evidence presently available regarding a possible predictive value of PIK3CA amplification for response to targeted treatment strategies, suggesting that this molecular alteration might represent an intriguing biomarker in this sense. Considering that few of the currently active clinical trials assessing agents targeting the PI3K/AKT/mTOR pathway in TNBC select patients based on tumor molecular characterization, and none of these based on PIK3CA copy number status, we urge for the introduction of PIK3CA amplification as a criterion for patient selection in future clinical trials in this setting.
- |||||||||| everolimus / Generic mfg.
Journal, IO biomarker: Everolimus attenuates glutamate-induced PC12 cells death. (Pubmed Central) - Mar 2, 2023 Also, EVR (40?nM) significantly (p?<?0.01) inhibited glutamate-induced apoptosis through depressing the elevation of bax/bcl-2 ratio and expression of cleaved caspase-3, concentration depend. The results demonstrated, for the first time, that EVR could protect against glutamate-mediated PC12 cell death via inhibiting apoptosis.
- |||||||||| everolimus / Generic mfg.
Trial completion date, Trial primary completion date, Surgery: EVEREST: S0931, Everolimus in Treating Patients With Kidney Cancer Who Have Undergone Surgery (clinicaltrials.gov) - Mar 2, 2023 P3, N=1545, Active, not recruiting, The results demonstrated, for the first time, that EVR could protect against glutamate-mediated PC12 cell death via inhibiting apoptosis. Trial completion date: Jan 2023 --> Jul 2023 | Trial primary completion date: Jan 2023 --> Jul 2023
- |||||||||| Mekinist (trametinib) / Novartis, BeiGene, Lenvima (lenvatinib) / Eisai, Merck (MSD)
Trial completion date, Trial primary completion date, Metastases: Trametinib Combined With Everolimus and Lenvatinib for Recurrent/Refractory Advanced Solid Tumors (clinicaltrials.gov) - Feb 28, 2023 P2, N=100, Recruiting, Notably, the early initiation of mTOR inhibitor treatment improved the long-term survival of HTx recipients compared with other combinations. Trial completion date: Jan 2025 --> Jan 2027 | Trial primary completion date: Jan 2023 --> Jan 2025
- |||||||||| Tagrisso (osimertinib) / AstraZeneca
Trial completion date, Trial primary completion date: Implantable Microdevice In Primary Brain Tumors (clinicaltrials.gov) - Feb 28, 2023 P1, N=12, Recruiting, Trial completion date: Jan 2025 --> Jan 2027 | Trial primary completion date: Jan 2023 --> Jan 2025 Trial completion date: Feb 2022 --> Feb 2024 | Trial primary completion date: Sep 2021 --> Sep 2023
- |||||||||| everolimus / Generic mfg., tacrolimus oral / Generic mfg., azathioprine / Generic mfg.
Journal: Immunosuppression in Uterus Transplantation: Experience From the Dallas Uterus Transplant Study. (Pubmed Central) - Feb 27, 2023 CFTR modulators in LTx patients with CF have minimum impact on calcineurin inhibitor level, most side effects were reversible within 2 weeks yet itch and muscle pain were notable. Our experience demonstrates that safe IS regimens can be used for uterus transplant recipients before and during pregnancy.
- |||||||||| metformin / Generic mfg., letrozole / Generic mfg., everolimus / Generic mfg.
Trial primary completion date, Metastases: A Phase II, Single-Arm Study of RAD001 (Everolimus), Letrozole, and Metformin in Patients With Advanced or Recurrent Endometrial Carcinoma (clinicaltrials.gov) - Feb 27, 2023 P2, N=62, Active, not recruiting, No PFS2 difference was found between different treatment sequences of TKI-TKI or TKI-immune therapy. Trial primary completion date: Oct 2022 --> Oct 2023
|