A first-in-human, first-in-class, phase (ph) I study of systemic Hedgehog (Hh) pathway antagonist, GDC-0449, in patients (pts) with advanced solid tumors

LoRusso, Patricia; Rudin, Charles M.; Borad, Mitesh J.; Vernillet, Laurent; Darbonne, Walter C.; Mackey, Howard M.; DiMartino, Jorge; Sauvage, Fred de; Low, Jennifer A.; Hoff, Daniel D. Von

doi:10.1200/jco.2008.26.15_suppl.3516

Cited by 27 publications

(23 citation statements)

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“…Other Smo-inhibiting synthetic molecules, such as GDC-449, IPI-926, Cur-61414 and BMS-833923 are also at pre-clinical and clinical stages. GDC-0449 has recently entered phase II clinical trials on recurrent medulloblastoma, glioma, gastric carcinoma, breast cancer, prostate carcinoma, lung carcinoma and others [36] (Table 2).…”

Section: Chemotherapeutic Agents Targeting Hedgehog Signalingmentioning

confidence: 99%

Novel Small Molecule Inhibitors of Cancer Stem Cell Signaling Pathways

Abetov

Mustapova

Saliev

et al. 2015

Stem Cell Rev and Rep

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The main aim of oncologists worldwide is to understand and then intervene in the primary tumor initiation and propagation mechanisms. This is essential to allow targeted elimination of cancer cells without altering normal mitotic cells. Currently, there are two main rival theories describing the process of tumorigenesis. According to the Stochastic Model, potentially any cell, once defunct, is capable of initiating carcinogenesis. Alternatively the Cancer Stem Cell (CSC) Model posits that only a small fraction of undifferentiated tumor cells are capable of triggering carcinogenesis. Like healthy stem cells, CSCs are also characterized by a capacity for self-renewal and the ability to generate differentiated progeny, possibly mediating treatment resistance, thus leading to tumor recurrence and metastasis. Moreover, molecular signaling profiles are similar between CSCs and normal stem cells, including Wnt, Notch and Hedgehog pathways. Therefore, development of novel chemotherapeutic agents and proteins (e.g., enzymes and antibodies) specifically targeting CSCs are attractive pharmaceutical candidates. This article describes small molecule inhibitors of stem cell pathways Wnt, Notch and Hedgehog, and their recent chemotherapy clinical trials. Original language EnglishPages (from-to) 909-918

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Section: Chemotherapeutic Agents Targeting Hedgehog Signalingmentioning

confidence: 99%

Novel Small Molecule Inhibitors of Cancer Stem Cell Signaling Pathways

Abetov

Mustapova

Saliev

et al. 2015

Stem Cell Rev and Rep

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“…This small synthetic molecule was discovered through a high-throughput screening of a library of chemical compounds to analyze their potential inhibitory effect on the GLI1 expression by luciferase reporter gene assays followed by an optimization of the pharmacological properties of the most active SMO antagonists by medicinal chemistry (Robarge et al, 2009). The data from a phase I multicenter clinical trial con-CRITICAL ROLES OF HEDGEHOG AND EGFR sisting of the administration of orally active GDC-0449 in patients with advanced and metastatic cancers revealed that this pharmacological agent showed antitumoral activity and was well tolerated, with no grade 5 adverse events and dose-limiting toxicity, in a subset of cancer patients (LoRusso et al, 2008;Molckovsky and Siu, 2008;Von Hoff et al, 2009). More specifically, the results from this phase I clinical trial, obtained with 33 patients diagnosed with locally advanced or metastatic BCCs that were refractory to standard therapies, treated daily with oral GDC-0449 during a median time of 9.8 months, revealed that two patients showed a complete tumor response and 16 had a partial response to this treatment, whereas other patients had stable or progressive disease (Von Hoff et al, 2009).…”

Section: Clinical Trials With the Canonical Hedgehog Cascade Inhibmentioning

confidence: 99%

Frequent Deregulations in the Hedgehog Signaling Network and Cross-Talks with the Epidermal Growth Factor Receptor Pathway Involved in Cancer Progression and Targeted Therapies

2010

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“…In April, 2009, Genentech and Curis announced interim Phase I results with GDC-0449 in patients with locally advanced, multifocal, or metastatic basal cell carcinoma [57]. Patients received dosages of 150, 270, or 540 mg of GDC-0449 orally as a single dose on Day 1 followed by a 1 week break and then daily continuous dosing beginning on Day 8 for a 28-day period.…”

Section: Clinical Datamentioning

confidence: 99%

The hedgehog pathway as a therapeutic target for treatment of breast cancer

Barginear

Leung

Budman

2009

Breast Cancer Res Treat

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The Hedgehog (Hh) signaling pathway plays a key role in a variety of processes, such as embryogenesis and maintenance of adult tissue homeostasis. It is also becoming increasingly clear that this pathway can have a crucial role in tumorigenesis. Most recently, the Hh signaling pathway has been implicated in the development and maintenance of breast cancer. Here we review Hh signaling, advances in small molecule and antibody-based inhibitors targeting the Hh pathway, and dysregulation of the Hh signaling pathway in breast cancer.

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A first-in-human, first-in-class, phase (ph) I study of systemic Hedgehog (Hh) pathway antagonist, GDC-0449, in patients (pts) with advanced solid tumors

Cited by 27 publications

References 0 publications

Novel Small Molecule Inhibitors of Cancer Stem Cell Signaling Pathways

Novel Small Molecule Inhibitors of Cancer Stem Cell Signaling Pathways

Frequent Deregulations in the Hedgehog Signaling Network and Cross-Talks with the Epidermal Growth Factor Receptor Pathway Involved in Cancer Progression and Targeted Therapies

The hedgehog pathway as a therapeutic target for treatment of breast cancer

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