Vismodegib: A smoothened inhibitor for the treatment of advanced basal cell carcinoma

Aditya, Suruchi; Rattan, Aditya

doi:10.4103/2229-5178.120685

Cited by 26 publications

(20 citation statements)

References 7 publications

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“…SMO has emerged as an important therapeutic target for several cancer types including breast cancer [ 39 ]. Two orally active SMO inhibitors, vismodegib (Erivedge) and sonidegib (Odzomo), received FDA approval for advanced basal cell carcinoma [ 40 , 41 ]. Our laboratory previously reported that JAK2-STAT3 and SMO-GLI1/tGLI1 pathways are concurrently activated in most TNBC and HER2-enriched tumors [ 42 ], the two subtypes of breast cancer associated with most aggressive clinical behaviors.…”

Section: Introductionmentioning

confidence: 99%

Combined inhibition of JAK2-STAT3 and SMO-GLI1/tGLI1 pathways suppresses breast cancer stem cells, tumor growth, and metastasis

et al. 2020

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Triple-negative breast cancer (TNBC) and HER2-positive breast cancer are particularly aggressive and associated with unfavorable prognosis. TNBC lacks effective treatments. HER2-positive tumors have treatment options but often acquire resistance to HER2-targeted therapy after initial response. To address these challenges, we determined whether novel combinations of JAK2-STAT3 and SMO-GLI1/tGLI1 inhibitors synergistically target TNBC and HER2 breast cancer since these two pathways are concurrently activated in both tumor types and enriched in metastatic tumors. Herein, we show that novel combinations of JAK2 inhibitors (ruxolitinib and pacritinib) with SMO inhibitors (vismodegib and sonidegib) synergistically inhibited in vitro growth of TNBC and HER2-positive trastuzumab-resistant BT474-TtzmR cells. Synergy was also observed against breast cancer stem cells. To determine if the combination is efficacious in inhibiting metastasis, we treated mice with intracardially inoculated TNBC cells and found the combination to inhibit lung and liver metastases, and prolong host survival without toxicity. The combination inhibited orthotopic growth, VEGF-A expression, and tumor vasculature of both TNBC and HER2-positive trastuzumab-refractory breast cancer. Lung metastasis of orthotopic BT474-TtzmR xenografts was suppressed by the combination. Together, our results indicated that dual targeting of JAK2 and SMO resulted in synergistic suppression of breast cancer growth and metastasis, thereby supporting future clinical testing.

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Section: Introductionmentioning

confidence: 99%

Combined inhibition of JAK2-STAT3 and SMO-GLI1/tGLI1 pathways suppresses breast cancer stem cells, tumor growth, and metastasis

et al. 2020

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“…Small molecule modulators of Hh signaling have been used in basic research for several years now to detect links between signaling and specific phenotypes of interest. Currently, CDC-0449 (Vismodegib) and LDE225 (Sonidegib), both Smoothened inhibitors, and arsenic trioxide (ATO), a Gli1/2 inhibitor, have been approved by the Food and Drug Administration (FDA) to treat basal cell carcinoma (BCC) and certain leukemias, respectively, whereas many others are still in clinical trials ( Figure 1 B) [ 3 , 119 , 120 ]. The idea that these approved and yet-to-be-approved molecules might be repurposed to have therapeutic value in humans beyond certain types of cancers is certainly worth exploring [ 24 ].…”

Section: Therapeutic Strategiesmentioning

confidence: 99%

The Hedgehog Signaling Pathway Emerges as a Pathogenic Target

Smelkinson

2017

JDB

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The Hedgehog (Hh) signaling pathway plays an essential role in the growth, development, and homeostatis of many tissues in vertebrates and invertebrates. Much of what is known about Hh signaling is in the context of embryonic development and tumor formation. However, a growing body of evidence is emerging indicating that Hh signaling is also involved in postnatal processes such as tissue repair and adult immune responses. To that extent, Hh signaling has also been shown to be a target for some pathogens that presumably utilize the pathway to control the local infected environment. In this review, we discuss what is currently known regarding pathogenic interactions with Hh signaling and speculate on the reasons for this pathway being a target. We also hope to shed light on the possibility of using small molecule modulators of Hh signaling as effective therapies for a wider range of human diseases beyond their current use in a limited number of cancers.

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“…Development of therapeutics regarding the Shh signaling pathway has primarily focused on targeting Smo and Gli. Preclinical experiments have already shown efficacy of single-agent Smo inhibitors in some malignancies, while two of these active agents have received FDA approval for treating advanced or metastatic basal cell carcinoma [42]. In addition, Shh inhibitors have been shown to successfully inhibit the Shh pathway, although they have not reached the clinic yet.…”

Section: Discussionmentioning

confidence: 99%

Mismatch repair deficiency and aberrations in the Notch and Hedgehog pathways are of prognostic value in patients with endometrial cancer

et al. 2018

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The aim of this study was to investigate the prognostic value of the Hedgehog (Gli, Patched-1, Shh, Smo) and Notch (Jag1, Notch2, Notch3) pathway members, in comparison to a panel of proteins (ER, PgR, HER2/neu, Ki67, p53, p16, PTEN and MMR) previously suggested to be involved in the pathogenesis of endometrial cancer, in association with clinical outcome and standard clinicopathological characteristics. A total of 204 patients with histological diagnosis of endometrial cancer treated from 2004 to 2013 were included. The evaluation of protein expression was assessed by immunohistochemistry. Univariate analysis showed that higher Ki67 labeling, expression of PTEN, p16, Notch2 and Notch3 proteins, as well as MMR proficiency were associated with increased relapse and mortality rate. Additionally, Patched-1 protein expression was associated with worse DFS, while p53 overexpression was associated with worse OS. In multivariate analyses, patients with MMR proficient tumors had more than double risk for death than patients with MMR deficient (MMRd) tumors (adjusted HR = 2.19, 95% CI 1.05–4.58, p = 0.036). Jag1 positivity conferred reduced mortality risk (HR = 0.48, 95% CI 0.23–0.97, p = 0.042). However, as shown by hierarchical clustering, patients fared better when their tumors expressed high Jag1 protein in the absence of Notch2 and Notch3, while they fared worse when all three proteins were highly expressed. Patched-1 positivity conferred higher risk for relapse (HR = 2.04, 95% CI 1.05–3.96, p = 0.036).Aberrant expression of key components of the Notch and Hedgehog signaling pathways, as well as MMRd may serve as independent prognostic factors for recurrence and survival in patients with endometrial cancer.

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Vismodegib: A smoothened inhibitor for the treatment of advanced basal cell carcinoma

Cited by 26 publications

References 7 publications

Combined inhibition of JAK2-STAT3 and SMO-GLI1/tGLI1 pathways suppresses breast cancer stem cells, tumor growth, and metastasis

Combined inhibition of JAK2-STAT3 and SMO-GLI1/tGLI1 pathways suppresses breast cancer stem cells, tumor growth, and metastasis

The Hedgehog Signaling Pathway Emerges as a Pathogenic Target

Mismatch repair deficiency and aberrations in the Notch and Hedgehog pathways are of prognostic value in patients with endometrial cancer

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