An Open-Label, Phase I, Dose Escalation Study Evaluating the Safety and Tolerability of GDC-0349 in Patients With Locally Advanced or Metastatic Solid Tumors or Non Hodgkin's Lymphoma

This is an open-label, multicenter, Phase I, dose-escalation study to assess the safety, tolerability, and pharmacokinetic (PK) of GDC-0349 administered once daily (QD), orally (PO).

Start Date01 Jun 2011

Sponsor / Collaborator

Genentech, Inc.

100 Clinical Results associated with GDC-0349

100 Translational Medicine associated with GDC-0349

100 Patents (Medical) associated with GDC-0349

Literatures (Medical) associated with GDC-0349

01 Nov 2024·eBioMedicine

Loss of heterozygosity of CYP2D6 enhances the sensitivity of hepatocellular carcinomas to talazoparib

Article

Author: Dupuis, Jordan ; Zhong, Lei ; Svensson, Richard ; Artursson, Per ; Heim, Markus H. ; Al Nassralla, Shahed ; Heim, Markus H ; Ljungström, Viktor ; Rendo, Verónica ; Kundu, Snehangshu ; Sjöblom, Tobias ; Stoimenov, Ivaylo ; Rameika, Natallia ; Nuciforo, Sandro ; Tsiara, Ioanna ; Seeburger, Pauline ; Al Azhar, Muhammad ; Veanes, Margus ; Globisch, Daniel ; Zhang, Xiaonan

BACKGROUNDLoss of heterozygosity (LOH) diminishes genetic diversity within cancer genomes. A tumour arising in an individual heterozygous for a functional and a loss-of-function (LoF) allele of a gene occasionally retain only the LoF allele. This can result in deficiency of specific protein activities in cancer cells, creating unique differences between tumour cells and normal cells of the individual. Such differences may constitute vulnerabilities that can be exploited through allele-specific therapies.METHODSTo discover frequently lost genes with prevalent LoF alleles, we mined the 1000 Genomes dataset for SNVs causing protein truncation through base substitution, indels or splice site disruptions, resulting in 60 LoF variants in 60 genes. From these, the variant rs3892097 in the liver enzyme CYP2D6 was selected because it is located within a genomic region that frequently undergoes LOH in several tumor types including hepatocellular cancers. To evaluate the relationship between CYP2D6 activity and the toxicities of anticancer agents, we screened 525 compounds currently in clinical use or undergoing clinical trials using cell model systems with or without CYP2D6 activity.FINDINGSWe identified 12 compounds, AZD-3463, CYC-116, etoposide, everolimus, GDC-0349, lenvatinib, MK-8776, PHA-680632, talazoparib, tyrphostin 9, VX-702, and WZ-3146, using an engineered HEK293T cell model. Of these, talazoparib and MK-8776 demonstrated consistently heightened cytotoxic effects against cells with compromised CYP2D6 activity in engineered hepatocellular cancer cell models. Moreover, talazoparib displayed CYP2D6 genotype dependent effects on primary hepatocellular carcinoma organoids.INTERPRETATIONExploiting the loss of drug-metabolizing enzyme gene activity in tumor cells following loss of heterozygosity could present a promising therapeutic strategy for targeted cancer treatment.FUNDINGThis work was funded by Barncancerfonden (T.S, PR2022-0099 and PR2020-0171, X.Z, TJ2021-0111), Cancerfonden (T.S, 211719Pj and D.G, 222449Pj), Vetenskapsrådet (T.S, 2020-02371 and D.G, 2020-04707), and the Erling Persson Foundation (T.S, 2020-0037 and T.S, 2023-0113).

01 Aug 2023·Nucleic Acid Therapeutics

mTOR Inhibition Enhances Delivery and Activity of Antisense Oligonucleotides in Uveal Melanoma Cells

Article

Author: Yigit, Nurten ; Mestdagh, Pieter ; Raemdonck, Koen ; Eyckerman, Sven ; Bogaert, Bram ; Dewaele, Shanna ; Nuytens, Justine ; Delhaye, Louis ; Martinez, Ramiro ; De Paepe, Boel ; Anckaert, Jasper ; Van Coster, Rudy

Uveal melanoma (UM) is the most common primary intraocular malignancy in adults. Owing to a lack of effective treatments, patients with metastatic disease have a median survival time of 6-12 months. We recently demonstrated that the Survival Associated Mitochondrial Melanoma Specific Oncogenic Non-coding RNA (SAMMSON) is essential for UM cell survival and that antisense oligonucleotide (ASO)-mediated silencing of SAMMSON impaired cell viability and tumor growth in vitro and in vivo. By screening a library of 2911 clinical stage compounds, we identified the mammalian target of rapamycin (mTOR) inhibitor GDC-0349 to synergize with SAMMSON inhibition in UM. Mechanistic studies revealed that mTOR inhibition enhanced uptake and reduced lysosomal accumulation of lipid complexed SAMMSON ASOs, improving SAMMSON knockdown and further decreasing UM cell viability. We found mTOR inhibition to also enhance target knockdown in other cancer cell lines as well as normal cells when combined with lipid nanoparticle complexed or encapsulated ASOs or small interfering RNAs (siRNAs). Our results are relevant to nucleic acid treatment in general and highlight the potential of mTOR inhibition to enhance ASO and siRNA-mediated target knockdown.

01 Apr 2021·Histology and histopathologyQ4 · BIOLOGY

Expression of long-chain noncoding RNA GAS5 in osteoarthritis and its effect on apoptosis and autophagy of osteoarthritis chondrocytes.

Q4 · BIOLOGY

Article

Author: Liu, Yongxiang ; Qiao, Xiaofeng ; Ji, Qinghui ; Wang, Dawei

OBJECTIVETo investigate the expression of long-chain noncoding RNA GAS5 in osteoarthritis (OA) and the effect of silencing GAS5 on autophagy of osteoarthritis chondrocytes (OACs).METHODSOA rat models were constructed by cutting the anterior cruciate ligament, and the expressions of GAS5 in rat cartilage tissues at 4 weeks (early OA) and 12 weeks (late OA) after modeling were detected. The rat chondrocytes were isolated, cultured and transfected with si-GAS5 to silencing GAS5. Then, the changes of apoptosis and autophagy levels of OA chondrocytes were detected by transfection of GFP-LC3 and flow cytometry. Bioinformatic tools were used to analyze the miRNA binding to GAS5 and the downstream target genes, then luciferase reporter assay and GDC-0349 (inhibitor of mTOR) were used to verify their relationships.RESULTSThe expression of GAS5 in cartilage tissue of OA rats was higher than control, which was higher in late OA than that in early OA. After silencing the GAS5, the autophagy ability of OACs was increased and the apoptosis rate was decreased. GAS5 was able to bind to miR-144 and regulate the expressin of mTOR. mTOR inhibitor GDC-0349 could reverse the inhibition of GAS5 on autophagy but could not reverse its effect on apoptosis.CONCLUSIONGAS5 expresses highly in OA cartilage tissues and increases with the progression of OA. GAS5 inhibits autophagy and promotes the apoptosis of OACs, and the inhibition of autophagy may be related to its regulation of mTOR.

100 Deals associated with GDC-0349

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R&D Status

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Indication	Highest Phase	Country/Location	Organization	Date
Solid tumor	Phase 2	US	Genentech, Inc.	01 Jun 2011
Solid tumor	Phase 2	CA	Genentech, Inc.	01 Jun 2011
Non-Hodgkin Lymphoma	Phase 2	-	Genentech, Inc.	-
Non-Hodgkin Lymphoma	Phase 2	-	Genentech, Inc.	-

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