Phase I Safety and Pharmacokinetic Study of the PI3K/mTOR Inhibitor SAR245409 (XL765) in Combination with Erlotinib in Patients with Advanced Solid Tumors

Jänne, Pasi A.; Cohen, Roger B.; Laird, A. Douglas; Macé, Sandrine; Engelman, Jeffrey A.; Ruiz-Soto, Rodrigo; Rockich, Kevin; Xu, Jianbo; Shapiro, Geoffrey I.; Martı́nez, Pablo; Felip, Enriqueta

doi:10.1097/jto.0000000000000088

Cited by 45 publications

(24 citation statements)

References 20 publications

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“…As expected, these inhibitors overcome the limitations of rapalogs and inhibit mTORC2-independent activation of AKT, while providing superior blockade of resurgent PI3K activity. Unfortunately, Phase I clinical trials using PI3K/mTOR dual kinase inhibitors revealed significant dose-limiting on-target toxicities (94,95), consistent with the important roles these enzymes fulfill in homeostasis of healthy tissues and systemic metabolism.…”

Section: Mtor Inhibitors For Cancer Therapymentioning

confidence: 91%

mTORC1 and mTORC2 in cancer and the tumor microenvironment

2016

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The mammalian target of rapamycin (mTOR) is a crucial signaling node that integrates environmental cues to regulate cell survival, proliferation, and metabolism, and is often deregulated in human cancer. mTOR kinase acts in two functionally distinct complexes, mTOR complex 1 (mTORC1) and 2 (mTORC2), whose activities and substrate specificities are regulated by complex co-factors. Deregulation of this centralized signaling pathway has been associated with a variety of human diseases including diabetes, neurodegeneration, and cancer. While mTORC1 signaling has been extensively studied in cancer, recent discoveries indicate a subset of human cancers harboring amplifications in mTORC2-specific genes as the only actionable genomic alterations, suggesting a distinct role for mTORC2 in cancer as well. This review will summarize recent advances in dissecting the relative contributions of mTORC1 versus mTORC2 in cancer, their role in tumor-associated blood vessels and tumor immunity, and provide an update on mTOR inhibitors.

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Section: Mtor Inhibitors For Cancer Therapymentioning

confidence: 91%

mTORC1 and mTORC2 in cancer and the tumor microenvironment

2016

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“…To distinguish it from the types of residual disease discussed above in which the targeted agent reaches the intended target in cells, this type of failure can arise via the presence of drug efflux pumps in tumor cells and stromal and physical barriers that restrict drug delivery, resulting in insufficient drug concentrations to impact the intended tumor therapeutic target (Figure 2) 40,41 . Pharmacokinetic failure due to pharmacologic limitations in drug solubility, distribution, concentration, and dose-limiting toxicity can also result in incomplete suppression of the targeted pathway, resulting in insufficient pathway blockade and residual disease in vivo 39,42 . An example is the lack of CNS-penetration and activity of many targeted agents in clinical use such as certain inhibitors of EGFR (such as erlotinib) and ALK (such as crizotinib), resulting in CNS disease persistence that is strikingly different from extra-cranial tumor response (albeit typically incomplete) in patients 43.…”

Section: The Presence and Etiology Of Residual Diseasementioning

confidence: 99%

“…Therapies to overcome targeted therapy resistance are typically tested in the second-line treatment setting, in patients who have failed first-line treatment (Table 1) 4645, 47 . However, in many cases second-line polytherapy against the primary oncogene target plus a critical bypass track component has shown muted clinical efficacy, as exemplified by results from clinical trials testing EGFR plus PI3K ( phosphoinositide 3-kinase ) inhibitor treatment in lung cancer (Table 1) 49504251 . An example of the potential importance of utilizing rational polytherapy as a first-line therapeutic strategy is the use of BRAF inhibitor plus MEK inhibitor polytherapy in BRAF V600E -mutant melanoma patients to overcome the re-activation of RAF-MEK-ERK signaling that can occur during BRAF inhibitor monotherapy and cause resistance to BRAF inhibition alone 5214 .…”

Section: Targeting Residual Diseasementioning

confidence: 99%

A framework for understanding and targeting residual disease in oncogene-driven solid cancers

Bivona

Doebele

2016

Nat Med

152

187

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Molecular targeted therapy has the potential to dramatically improve cancer patient survival. However, complete and durable responses to targeted therapy are rare in advanced-stage solid cancer patients. Even the most effective targeted therapies generally do not induce a complete tumor response, resulting in residual disease and tumor progression that limits patient survival. We discuss the emerging need to more fully understand the molecular basis of residual disease as a prelude to designing principled therapeutic strategies to minimize or eliminate it so that we can move from temporary to chronic control or cure in advanced-stage solid cancer patients. Ultimately, we propose a shift from the current reactive paradigm of analyzing and treating acquired drug resistance to a pre-emptive paradigm of defining the mechanisms of residual disease in order to target and limit this disease reservoir.

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“…Moreover, BEZ235 and the lysosomotropic agent chloroquine synergize to trigger apoptosis in neuroblastoma cells via mitochondrial-lysosomal cross-talk (48). SAR245409 (also known as XL765), another PI3K/mTOR inhibitor, was shown to inhibit proliferation and induce apoptosis in various tumor cell lines (49), in mouse xenograft models (50) and in patients with advanced solid tumors (51,52). Perifosine, a pan-Akt inhibitor of PIP 3 binding, possesses antitumor growth effect alone or in combination with chemotherapy in neuroblastoma (53).…”

Section: Amp-activated Protein Kinase (Ampk) Is Inhibited Upon the 14mentioning

confidence: 99%

GD2 ganglioside specific antibody treatment downregulates PI3K/Akt/mTOR signaling network in human neuroblastoma cell lines

Durbas

Horwacik

Boratyn

et al. 2015

International Journal of Oncology

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Abstract. Mechanisms leading to inhibitory effects of an anti-GD2 ganglioside (GD2) 14G2a mouse monoclonal antibody (mAb) and PI3K/Akt/mTOR pathway inhibitors on human neuroblastoma cell survival were studied in vitro. We have recently shown on IMR-32, CHP-134, and LA-N-1 neuroblastoma cells that targeting GD2 with the mAb decreases cell viability of the cell lines. In this study we used cytotoxicity assays, proteomic arrays and immunoblotting to evaluate the response of the three cell lines to the anti-GD2 14G2a mAb and specific PI3K/Akt/mTOR pathway inhibitors. We show here that the mAb modulates intracellular signal transduction through changes in several kinases and their substrates phosphorylation. More detailed analysis of the PI3K/Akt/ mTOR pathway showed significant decrease in activity of Akt, mTOR, p70 S6 and 4E-BP1 proteins and transient increase in PTEN (a suppressor of the pathway), leading to inhibition of the signaling network responsible for stimulation of translation and proliferation. Additionally, combining the GD2-specific 14G2a mAb with an Akt inhibitor (perifosine), dual mTOR/PI3K inhibitors (BEZ-235 and SAR245409), and a pan-PI3K inhibitor (LY294002) was shown to enhance cytotoxic effects against IMR-32, CHP-134 and LA-N-1 cells. Our study extends knowledge on mechanisms of action of the 14G2a mAb on the neuroblastoma cells. Also, it stresses the need for further delineation of molecular signal orchestration aimed at more reasonable selection of drugs to target key cellular pathways in quest for better cure for neuroblastoma patients.

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Phase I Safety and Pharmacokinetic Study of the PI3K/mTOR Inhibitor SAR245409 (XL765) in Combination with Erlotinib in Patients with Advanced Solid Tumors

Abstract: MTDs of SAR245409 and erlotinib were below the single-agent doses of either agent, despite the lack of major pharmacokinetic interaction.

Cited by 45 publications

References 20 publications

mTORC1 and mTORC2 in cancer and the tumor microenvironment

mTORC1 and mTORC2 in cancer and the tumor microenvironment

A framework for understanding and targeting residual disease in oncogene-driven solid cancers

GD2 ganglioside specific antibody treatment downregulates PI3K/Akt/mTOR signaling network in human neuroblastoma cell lines

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