This phenotype was further exacerbated by chronic temozolomide treatment in both in vitro and in vivo glioblastoma models. Notably, CMA-activating compounds, including the RARA (retinoic acid receptor alpha) antagonist CA77.1, the class I phosphoinositide 3-kinase (PI3K) inhibitor paxalisib, and metformin, effectively reduced IDH1 and CCND1 levels while suppressing glioblastoma cell growth. Together, our findings suggest that dysfunction of the CMA-IDH1-CCND1 regulatory cascade drives progression of IDH1-wild-type glioblastoma and provide a mechanistic basis for repurposing CMA activators as potential therapeutic agents for these tumors.

22 days ago

Journal

IDH1 (Isocitrate dehydrogenase (NADP(+)) 1) • RB1 (RB Transcriptional Corepressor 1) • CCND1 (Cyclin D1) • RARA (Retinoic Acid Receptor Alpha) • HSPA8 (Heat Shock Protein Family A (Hsp70) Member 8)

IDH wild-type

temozolomide • metformin • paxalisib (GDC-0084)

Synthesis and evaluation of pyrimidine derivatives for Glioblastoma Multiforme inhibition. (PubMed, Biochem Biophys Res Commun)

In an orthotopic transplantation GBM model, compared with GDC-0084, KJ-25 significantly suppressed tumor growth. These results suggest that KJ-25 is a promising candidate drug for the treatment of GBM, providing a strategy for improving the prognosis of this refractory malignant tumor.

1 month ago

Journal

HRAS (Harvey rat sarcoma viral oncogene homolog)

paxalisib (GDC-0084)

3ms

Genetic Testing in Guiding Treatment for Patients With Brain Metastases (clinicaltrials.gov)

P2, N=186, Suspended, Alliance for Clinical Trials in Oncology | Recruiting --> Suspended

3 months ago

Trial suspension

KRAS (KRAS proto-oncogene GTPase) • BRAF (B-raf proto-oncogene) • ER (Estrogen receptor) • PGR (Progesterone receptor) • ROS1 (Proto-Oncogene Tyrosine-Protein Kinase ROS) • NTRK (Neurotrophic receptor tyrosine kinase)

HER-2 positive • EGFR mutation • HER-2 negative • BRAF positive

Rozlytrek (entrectinib) • Verzenio (abemaciclib) • Krazati (adagrasib) • paxalisib (GDC-0084)

4ms

GBM AGILE: A Trial to Evaluate Multiple Regimens in Newly Diagnosed and Recurrent Glioblastoma (clinicaltrials.gov)

P2/3, N=1280, Recruiting, Global Coalition for Adaptive Research | Trial completion date: Jun 2028 --> Jun 2030 | Trial primary completion date: Jun 2026 --> Jun 2028

4 months ago

Trial completion date • Trial primary completion date

IDH wild-type

temozolomide • Stivarga (regorafenib) • lomustine • VT1021 • AZD1390 • Hepacid (pegargiminase) • paxalisib (GDC-0084) • dianhydrogalactitol (VAL-083) • Vyglxia (troriluzole)

4ms

PNOC022: Combination Therapy for the Treatment of Diffuse Midline Gliomas (clinicaltrials.gov)

P2, N=360, Recruiting, University of California, San Francisco | Trial primary completion date: Dec 2025 --> Dec 2027

4 months ago

Trial primary completion date

BRAF (B-raf proto-oncogene)

sirolimus • Modeyso (dordaviprone) • paxalisib (GDC-0084)

5ms

Paxalisib Plus Olaparib or Pembrolizumab/Chemotherapy in Advanced Breast Cancer (ACTRN12624001340527)

P1, N=24, Recruiting, Kazia Therapeutics | Not yet recruiting --> Recruiting

5 months ago

Enrollment open • Trial initiation date

HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset)

HER-2 negative

Keytruda (pembrolizumab) • Lynparza (olaparib) • carboplatin • albumin-bound paclitaxel • paxalisib (GDC-0084)

6ms

Depleting the action of EZH2 through PI3K-mTOR inhibition to overcome metastasis and immunotherapy resistance in triple-negative breast cancer. (PubMed, Mol Cancer Ther)

Dual PI3K-mTOR inhibition with paxalisib not only promotes a favorable mesenchymal to epithelial phenotype but also inhibits signatures associated with MICs, including the highly aggressive CSC phenotype, persister cancer cell phenotype (p65, FOXQ1, NRF2, NNMT), and a cancer drug resistance signature (ABCB5, SNAIL, ALDH1)...PI3K-mTOR blockade acts upstream of EZH2, impacting both the classical repressive catalytic p85β-EZH2-H27ME3 and active EZH2-NFκB pathways. Our data suggest that dual targeting of the PI3K-mTOR pathway disrupts both the catalytic and non-catalytic axes of EZH2 to inhibit metastasis and enhance cancer immune visibility, potentially increasing the utility of immunotherapy in resistant individuals.

6 months ago

Journal • IO biomarker

ALDH1A1 (Aldehyde Dehydrogenase 1 Family Member A1) • NNMT (Nicotinamide N-Methyltransferase)

paxalisib (GDC-0084)

8ms

GDC-0084 With Radiation Therapy for People With PIK3CA-Mutated Solid Tumor Brain Metastases or Leptomeningeal Metastases (clinicaltrials.gov)

P1, N=21, Active, not recruiting, Memorial Sloan Kettering Cancer Center | Trial completion date: Dec 2025 --> Dec 2026 | Trial primary completion date: Dec 2025 --> Dec 2026

8 months ago

Trial completion date • Trial primary completion date

PIK3CA (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha) • PTEN (Phosphatase and tensin homolog) • AKT1 (V-akt murine thymoma viral oncogene homolog 1) • PIK3R1 (Phosphoinositide-3-Kinase Regulatory Subunit 1) • PIK3CG (Phosphatidylinositol-4,5-Bisphosphate 3-Kinase Catalytic Subunit Gamma) • PIK3CD (Phosphatidylinositol-4 5-Bisphosphate 3-Kinase Catalytic Subunit Delta) • PIK3CB (Phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit beta) • INPP4B (Inositol polyphosphate-4-phosphatase type II B) • AKT2 (V-akt murine thymoma viral oncogene homolog 2) • INPP5D (Inositol Polyphosphate-5-Phosphatase D) • PIK3C3 (Phosphatidylinositol 3-Kinase Catalytic Subunit Type 3) • PIK3R2 (Phosphoinositide-3-Kinase Regulatory Subunit 2 ) • PIK3R3 (Phosphoinositide-3-Kinase Regulatory Subunit 3)

paxalisib (GDC-0084)

11ms

Paxalisib With a High Fat, Low Carb Diet and Metformin for Glioblastoma (clinicaltrials.gov)

P2, N=33, Recruiting, Weill Medical College of Cornell University | Trial primary completion date: Dec 2024 --> Dec 2025

11 months ago

Trial primary completion date

MGMT (6-O-methylguanine-DNA methyltransferase)

MGMT promoter methylation

metformin • paxalisib (GDC-0084)

11ms

Genetic Testing in Guiding Treatment for Patients with Brain Metastases (clinicaltrials.gov)

P2, N=186, Recruiting, Alliance for Clinical Trials in Oncology | Trial completion date: Jun 2026 --> Jun 2028 | Trial primary completion date: Oct 2025 --> Oct 2026

11 months ago

Trial completion date • Trial primary completion date

HER-2 positive • EGFR mutation • HER-2 negative • ROS1 mutation • BRAF positive

Rozlytrek (entrectinib) • Verzenio (abemaciclib) • Krazati (adagrasib) • paxalisib (GDC-0084)

11ms

Genetic Testing in Guiding Treatment for Patients With Brain Metastases (clinicaltrials.gov)

P2, N=186, Recruiting, Alliance for Clinical Trials in Oncology | Trial completion date: Jun 2025 --> Jun 2026 | Trial primary completion date: Oct 2024 --> Oct 2025

11 months ago

Trial completion date • Trial primary completion date

HER-2 positive • EGFR mutation • HER-2 negative • ROS1 mutation • BRAF positive

Rozlytrek (entrectinib) • Verzenio (abemaciclib) • Krazati (adagrasib) • paxalisib (GDC-0084)

1year

Paxalisib Plus Olaparib or Pembrolizumab/Chemotherapy in Advanced Breast Cancer (ACTRN12624001340527)

P1, N=24, Not yet recruiting, Kazia Therapeutics

1 year ago

New P1 trial • Metastases

HER-2 (Human epidermal growth factor receptor 2) • PD-L1 (Programmed death ligand 1) • BRCA1 (Breast cancer 1, early onset) • BRCA2 (Breast cancer 2, early onset)

HER-2 negative

Keytruda (pembrolizumab) • Lynparza (olaparib) • carboplatin • albumin-bound paclitaxel • paxalisib (GDC-0084)