Timothy F. Cloughesy

Nov 21, 2024 | nature.com | Wilson X. Mai |Kai Song |Nicholas Bayley |Jiyoon Kim |Henan Zhu |Pauline Young | +14 more

Genomic profiling often fails to predict therapeutic outcomes in cancer. This failure is, in part, due to a myriad of genetic alterations and the plasticity of cancer signaling networks. Functional profiling, which ascertains signaling dynamics, is an alternative method to anticipate drug responses. It is unclear whether integrating genomic and functional features of solid tumours can provide unique insight into therapeutic vulnerabilities. We perform combined molecular and functional characterization, via BH3 profiling of the intrinsic apoptotic machinery, in glioma patient samples and derivative models. We identify that standard-of-care therapy rapidly rewires apoptotic signaling in a genotype-specific manner, revealing targetable apoptotic vulnerabilities in gliomas containing specific molecular features (e.g., TP53 WT). However, integration of BH3 profiling reveals high mitochondrial priming is also required to induce glioma apoptosis. Accordingly, a machine-learning approach identifies a composite molecular and functional signature that best predicts responses of diverse intracranial glioma models to standard-of-care therapies combined with ABBV-155, a clinical drug targeting intrinsic apoptosis. This work demonstrates how complementary functional and molecular data can robustly predict therapy-induced cell death. Genomic profiling of tumours can help tailer treatments to the patient, however, it often fails to accurately predict therapeutic outcomes. Here, the authors combine molecular and functional characterisation via BH3 profiling to identify therapeutically targetable vulnerabilities in glioma.

Aug 13, 2024 | targetedonc.com | Timothy F. Cloughesy

Timothy F. Cloughesy, MD, director of UCLA’s neuro-oncology program and distinguished professor in neurology, discusses the mechanism of action of vorasidenib (Voranigo, formerly AG-881), the first oral, selective, highly brain-penetrant dual inhibitor of mutant IDH1 and IDH2 enzymes approved by the FDA for the treatment of patients with grade 2 astrocytoma or oligodendroglioma with a susceptible IDH1 or IDH2 mutation.

Aug 6, 2024 | targetedonc.com | Timothy F. Cloughesy

Timothy F. Cloughesy, MD, director of UCLA’s Neuro-Oncology Program, a distinguished professor in neurology, discusses the impact and significance of the FDA’s approval of vorasidenib (Voranigo, formerly AG-881), a first-in-class option for the treatment of patients with IDH-mutant gliomas. Vorasidenib is an oral, selective, highly brain-penetrant dual inhibitor of mutant IDH1 and IDH2 enzymes.

May 8, 2024 | nature.com | Richard Everson |Willy Hugo |Lu O. Sun |Joseph K. Antonios |Melissa Bu |Sara Khattab | +9 more

In this randomized phase II clinical trial, we evaluated the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to autologous tumor lysate-pulsed dendritic cell (ATL-DC) vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas. The primary endpoints were to assess the most effective combination of vaccine and adjuvant in order to enhance the immune potency, along with safety. The combination of ATL-DC vaccination and TLR agonist was safe and found to enhance systemic immune responses, as indicated by increased interferon gene expression and changes in immune cell activation. Specifically, PD-1 expression increases on CD4+ T-cells, while CD38 and CD39 expression are reduced on CD8+ T cells, alongside an increase in monocytes. Poly-ICLC treatment amplifies the induction of interferon-induced genes in monocytes and T lymphocytes. Patients that exhibit higher interferon response gene expression demonstrate prolonged survival and delayed disease progression. These findings suggest that combining ATL-DC with poly-ICLC can induce a polarized interferon response in circulating monocytes and CD8+ T cells, which may represent an important blood biomarker for immunotherapy in this patient population.Trial Registration: ClinicalTrials.gov Identifier: NCT01204684. Autologous tumor lysate (ATL) dendritic cell (DC) vaccination can induce local and systemic anti-tumor immune responses in malignant glioma patients. In this randomized phase II clinical trial, the authors evaluate the effectiveness of adding the TLR agonists, poly-ICLC or resiquimod, to ATL-DC vaccination in patients with newly-diagnosed or recurrent WHO Grade III-IV malignant gliomas.

Jul 24, 2023 | nature.com | Ian F. Parney |Solmaz Sahebjam |Nader Sanai |Michael Platten |Michael Lim |Timothy F. Cloughesy | +11 more

A breakthrough in drug discovery for glioblastoma requires serial collection of tissue from the central nervous system via window of opportunity trials Therapeutic drug development in glioblastoma has remained static despite numerous clinical trials, advances in tumor biology, and substantial public interest. Since 2005, more than 1,250 interventional glioblastoma trials have been registered on ClinicalTrials.gov.