First-in-Human Phase I Study to Evaluate the Brain-Penetrant PI3K/mTOR Inhibitor GDC-0084 in Patients with Progressive or Recurrent High-Grade Glioma

Wen, Patrick Y.; Cloughesy, Timothy F.; Olivero, Alan G.; Morrissey, Kari M.; Wilson, Timothy R.; Lu, Xuyang; Müeller, Lars; Coimbra, Alexandre Fernandez; Ellingson, Benjamin M.; Gerstner, Elizabeth R.; Lee, Eudocia Q.; Rodón, Jordi

doi:10.1158/1078-0432.ccr-19-2808

Cited by 60 publications

(45 citation statements)

References 38 publications

(25 reference statements)

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“…Subsequently, other PI3K/mTOR dual-targeting inhibitors include GDC-0980 (apitolisib), XL765, PF-04691502 (gedatolisib), PF-05212384 (PKI-587) and GSK2126458 (omipalisib), and they all showed favourable results in preclinical studies but alas faltered in clinical trials in terms of both toxicities and percentage effectiveness in patients ( Table 1 ) [ 48 , 57 ]. A bright spot for this family of inhibitors may be GDC-0084 (paxalisib) which has been shown to delay the progression of newly diagnosed glioblastoma, with manageable adverse side effects [ 80 , 81 ]. Currently, there are no dual inhibitors approved for clinical use.…”

Section: Pharmacological Targeting Of the Pi3k Pathwaymentioning

confidence: 99%

“…Buparlisib has the ability to permeate the blood–brain barrier (BBB) suggesting it could be beneficial for targeting various brain malignancies, but has the tendency to cause mood changes [ 83 , 87 ]. Pictilisib, on the other hand, barely penetrated tumours in models with intact BBB potentially explaining the lack of associated mood changes [ 80 , 88 ]. Both buparlisib and pictilisib have had less success in terms of clinical trials; however, both display favourable pharmacokinetic properties suggesting combination therapies may be a potential future use of this compound [ 82 , 89 , 90 ].…”

Section: Pharmacological Targeting Of the Pi3k Pathwaymentioning

confidence: 99%

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Mechanisms of Resistance to PI3K Inhibitors in Cancer: Adaptive Responses, Drug Tolerance and Cellular Plasticity

Wright

Vasilevski

Serra

et al. 2021

Cancers

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The phosphatidylinositol-3-kinase (PI3K) pathway plays a central role in the regulation of several signalling cascades which regulate biological processes such as cellular growth, survival, proliferation, motility and angiogenesis. The hyperactivation of this pathway is linked to tumour progression and is one of the most common events in human cancers. Additionally, aberrant activation of the PI3K pathway has been demonstrated to limit the effectiveness of a number of anti-tumour agents paving the way for the development and implementation of PI3K inhibitors in the clinic. However, the overall effectiveness of these compounds has been greatly limited by inadequate target engagement due to reactivation of the pathway by compensatory mechanisms. Herein, we review the common adaptive responses that lead to reactivation of the PI3K pathway, therapy resistance and potential strategies to overcome these mechanisms of resistance. Furthermore, we highlight the potential role in changes in cellular plasticity and PI3K inhibitor resistance.

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Section: Pharmacological Targeting Of the Pi3k Pathwaymentioning

confidence: 99%

Section: Pharmacological Targeting Of the Pi3k Pathwaymentioning

confidence: 99%

Mechanisms of Resistance to PI3K Inhibitors in Cancer: Adaptive Responses, Drug Tolerance and Cellular Plasticity

Wright

Vasilevski

Serra

et al. 2021

Cancers

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“…Alpelisib monotherapy is unavailable in all breast cancer, and it needs to combine with fulvestrant for its therapeutic effect [81,82]. Paxalisib prolongs 5 months overall survival (OS) than TMZ, independent of PI3K mutation status [83,84]. In HNSCC, only BKM120 monotherapy was applied in the clinical trial (NCT01737450).…”

Section: Pi3k Inhibitors Are Promising But Still Have a Long Way To Gomentioning

confidence: 99%

Therapeutic strategies of different HPV status in Head and Neck Squamous Cell Carcinoma

Sun¹,

Wang²,

Qiu³

et al. 2021

Int. J. Biol. Sci.

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Head and neck squamous cell carcinoma (HNSCC) is the 9 th most common malignant tumor in the world. Based on the etiology, HNSCC has two main subtypes: human papillomavirus (HPV)-related and HPV-unrelated. HPV-positive HNSCC is more sensitive to treatment with favorable survival. Due to the different biological behaviors, individual therapy is necessary and urgently required to deduce the therapeutic intensity of HPV-positive disease and look for a more effective and toxicity-acceptable regimen for HPV-negative disease. EGFR amplification and PI3K/AKT/mTOR pathway aberrant activation are quite common in HPV-positive HNSCC. Besides, HPV infection alters immune cell infiltrating in HNSCC and encompasses a diverse and heterogeneous landscape with more immune infiltration. On the other hand, the chance of HPV-negative cancers harboring mutation on the P53 gene is significantly higher than that of HPV-positive disease. This review focuses on the updated preclinical and clinical data of HPV-positive and HPV-negative HNSCC and discusses the therapeutic strategies of different HPV status in HNSCC.

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“…For pediatric patients harboring such a mutation, the targeted utilization of everolimus has been applied and, more recently, LY3023414, a dual PI3K and mTOR inhibitor, is undergoing investigation (NCT03213678). Furthermore, paxalisib (GDC-0084) is another PI3K/mTOR inhibitor, which has recently proven to penetrate the blood-brain barrier and showed a metabolic partial response, by FDG-PET, in up to 26% of adult HGG patients [65]. A firstin-pediatric study is currently examining the safety and preliminary antitumor activity of paxalisib in DMGs (NCT03696355).…”

Section: Braf Mutation and Braf/mek Inhibitorsmentioning

confidence: 99%

Advances in Targeted Therapies for Pediatric Brain Tumors

Mueller

Stücklin

Postlmayr

et al. 2020

Curr Treat Options Neurol

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Purpose of Review Over the last years, our understanding of the molecular biology of pediatric brain tumors has vastly improved. This has led to more narrowly defined subgroups of these tumors and has created new potential targets for molecularly driven therapies. This review presents an overview of the latest advances and challenges of implementing targeted therapies into the clinical management of pediatric brain tumors, with a focus on gliomas, craniopharyngiomas, and medulloblastomas. Recent Findings Pediatric low-grade gliomas (pLGG) show generally a low mutational burden with the mitogen-activated protein kinase (MAPK) signaling presenting a key driver for these tumors. Direct inhibition of this pathway through BRAF and/or MEK inhibitors has proven to be a clinically relevant strategy. More recently, MEK and IL-6 receptor inhibitors have started to be evaluated in the treatment for craniopharyngiomas. Aside these low-grade tumors, pediatric high-grade gliomas (pHGG) and medulloblastomas exhibit substantially greater molecular heterogeneity with various and sometimes unknown tumor driver alterations. The clinical benefit of different targeted therapy approaches to interfere with altered signaling pathways and restore epigenetic dysregulation is undergoing active clinical testing. For these multiple pathway-driven tumors, combination strategies will most likely be required to achieve clinical benefit. Summary The field of pediatric neuro-oncology made tremendous progress with regard to improved diagnosis setting the stage for precision medicine approaches over the last decades. The potential of targeted therapies has been clearly demonstrated for a subset of pediatric brain tumors. However, despite clear response rates, questions of sufficient blood-brain barrier penetration, optimal dosing, treatment duration as well as mechanisms of resistance and how these can be overcome with potential combination strategies need to be addressed in future investigations. Along this line, it is critical for future trials to define appropriate endpoints to assess therapy responses as well as short and long-term toxicities in the growing and developing child.

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First-in-Human Phase I Study to Evaluate the Brain-Penetrant PI3K/mTOR Inhibitor GDC-0084 in Patients with Progressive or Recurrent High-Grade Glioma

Cited by 60 publications

References 38 publications

Mechanisms of Resistance to PI3K Inhibitors in Cancer: Adaptive Responses, Drug Tolerance and Cellular Plasticity

Mechanisms of Resistance to PI3K Inhibitors in Cancer: Adaptive Responses, Drug Tolerance and Cellular Plasticity

Therapeutic strategies of different HPV status in Head and Neck Squamous Cell Carcinoma

Advances in Targeted Therapies for Pediatric Brain Tumors

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