Dose-Escalation Study of Sonidegib (Lde225) Plus Buparlisib (Bkm120) in Patients (Pts) with Advanced Solid Tumors

Chu, Quincy Siu-Chung; Mahipal, Amit; Schüler, Martin; Braud, F.G.M. De; Dirix, Luc; Rampersad, Anita; Zhou, Jocelyn; Wu, Ying; Kalambakas, Stacey; Wen, Patrick Y.

doi:10.1093/annonc/mdu331.5

Cited by 10 publications

(8 citation statements)

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“…To address the limited single-agent activity of Hh pathway inhibitors, combination therapy, concurrently targeting other upregulated signaling pathways, may be promising. For example, a combination of sonidegib and PI3K inhibitor buparlisib is currently under evaluation for patients with advanced solid tumors [85]. Along the same line, the strategy of using a single gene expression panel for patient selection, as used in previous medulloblastoma studies, is no longer valid in the setting of complex signaling responses, and a well-recognized presence of tumor heterogeneity.…”

Section: Discussionmentioning

confidence: 99%

Recent Advances in the Clinical Targeting of Hedgehog/GLI Signaling in Cancer

Xie

Paradise

Wee

et al. 2019

Cells

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The Hedgehog/GLI signaling pathway plays an important role in normal embryonic tissue development and has been implicated in the pathogenesis of various human cancers. In this review article, we summarize pre-clinical evidence supporting the suitability of targeting this signaling pathway in cancers. We review agents blocking both the ligand-dependent and ligand-independent cascades, and discuss the clinical evidence, which has led to the FDA approval of Hedgehog receptor Smoothened inhibitors, vismodegib, and sonidegib, in different malignancies. Finally, we provide an overview of published and ongoing clinical trial data on single agent or combination therapeutic strategies, targeting Hedgehog/GLI signaling pathway, in both advanced solid tumors and hematologic malignancies.

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Section: Discussionmentioning

confidence: 99%

Recent Advances in the Clinical Targeting of Hedgehog/GLI Signaling in Cancer

Xie

Paradise

Wee

et al. 2019

Cells

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“…Recently, Petrova et al (2013) discovered that RU-SKI inhibits HH signaling blocking HHAT-mediated SHH palmitoylation. 5E1 (Ericson et al, 1996), an anti-SHH monoclonal (Berman et al, 2002;Geoerger et al, 2012;Romer et al, 2004) Basal cell carcinoma (BCC) ligand-independent mouse model; clinical trial (Migden et al, 2015;Sekulic et al, 2012;Xie et al, 1998) Rhabdomyosarcoma (RMS) ligand-independent mouse model; clinical trial (Hahn et al, 1998;Kieran et al, 2013) Pancreatic cancer ligand-dependent mouse model; clinical trial (Ko et al, 2016;Olive et al, 2009) Chronic myeloid leukemia (CML) ligand-dependent mouse model; clinical trial (Dierks et al, 2008;Martinelli et al, 2015) Multiple myeloma ligand-dependent mouse model; clinical trial (Dierks et al, 2007;Khan et al, 2015) Lymphoma ligand-dependent mouse model; clinical trial (Dierks et al, 2007;Tibes and Mesa, 2014) Breast cancer ligand-dependent human breast cancer cell line; clinical trial (Chu et al, 2014;Zhang et al, 2009) Prostate cancer ligand-dependent human prostate cancer cell line; clinical trial (Antonarakis et al, 2013;Karhadkar et al, 2004) Small cell lung cancer ligand-dependent human lung cancer cell line; clinical trial (Belani et al, 2013;Watkins et al, 2003) Colorectal cancer ligand-dependent human colorectal cancer cell line; clinical trial (Berlin et al, 2013;Monzo et al, 2006) Liver cancer ligand-dependent human hepatocellular carcinoma cell line (Huang et al, 2006) Stomach cancer ligand-dependent human gastric carcinoma cell line; clinical trial (Berman et al, 2003;Cohen et al, 2013) antibody, and robotnikinin (Stanton et al, 2009), a small molecule that physically interacts with SHH, interfere with SHH-PTCH1 interaction, thereby inhibiting HH signaling. Experiments in various developmental and cancer studies have confirmed the efficacy of 5E1 with sub-nanomolar inhibitory potency …”

Section: Strategies To Modulate Hh Signalingmentioning

confidence: 99%

Hedgehog Signaling: From Basic Biology to Cancer Therapy

Zhang

Sun

et al. 2017

Cell Chemical Biology

261

242

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The Hedgehog (HH) signaling pathway was discovered originally as a key pathway in embryonic patterning and development. Since its discovery, it has become increasingly clear that the HH pathway also plays important roles in a multitude of cancers. Therefore, HH signaling has emerged as a therapeutic target of interest for cancer therapy. In this review, we provide a brief overview of HH signaling and the key molecular players involved and offer an up-to-date summary of our current knowledge of endogenous and exogenous small molecules that modulate HH signaling. We discuss experiences and lessons learned from the decades-long efforts toward the development of cancer therapies targeting the HH pathway. Challenges to develop next-generation cancer therapies are highlighted.

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“…A Phase Ib trial of buparlisib and the Hedgehog pathway inhibitor sonidegib in patients with advanced solid tumors including BC was recently presented [58]. The combination, which was based on the evidence of coexisting aberrant activation of both pathways in several tumor models [59,60], resulted Buparlisib Expert Opin.…”

Section: With Investigational Drugsmentioning

confidence: 99%

Buparlisib, an oral pan-PI3K inhibitor for the treatment of breast cancer

Geuna

Milani

Martinello

et al. 2015

Expert Opinion on Investigational Drugs

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Overall, buparlisib is a safe and tolerable drug and, despite its peculiar toxicity profile, it is suitable for studies in combination with other anticancer agents in BC. Early-phase clinical trials in BC have provided evidence of antitumor activity. Several trials are being conducted in all the biological subsets of BC, including combinations with endocrine therapy, anti-HER2 agents, PARP-inhibitors and chemotherapy. While clinical results are eagerly awaited, biological material suitable for both genomic and non-genomic analyses is being collected. The authors expect an intense investigation of the potential biomarkers that explain response or resistance to buparlisib and inspire strategies to rationally explore the therapeutic potential of this drug.

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Dose-Escalation Study of Sonidegib (Lde225) Plus Buparlisib (Bkm120) in Patients (Pts) with Advanced Solid Tumors

Cited by 10 publications

References 0 publications

Recent Advances in the Clinical Targeting of Hedgehog/GLI Signaling in Cancer

Recent Advances in the Clinical Targeting of Hedgehog/GLI Signaling in Cancer

Hedgehog Signaling: From Basic Biology to Cancer Therapy

Buparlisib, an oral pan-PI3K inhibitor for the treatment of breast cancer

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