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Table 2 Pharmacologic inhibition of SMO in MF, leukemia, lymphoma, and MM preclinical models and cell lines

From: Targeting hedgehog signaling in myelofibrosis and other hematologic malignancies

Model

Inhibitor

Effect

Murine MF model[51]

Sonidegib (LDE225)

• Caused reduction of mutant allele burden in bone marrow, reduced bone marrow fibrosis, and reduced white blood cell and platelet counts when combined with ruxolitinib in comparison with ruxolitinib treatment alone

Murine CML models[65, 68]

Cyclopamine

• Reduced LSC numbers and secondary transplantation capacity in BCR-ABL+ cells

• Prolonged survival in treated mice, alone[68] or in combination with TKI therapy[65]

BCR-ABL+ cells[82–85]

Vismodegib (GDC-0449), sonidegib

• Inhibited cell growth, self-renewal, and serial transplantation

• Enhanced activity of BCR-ABL–targeted TKIs

• Enhanced control of TKI-resistant cells[83, 84]

AML cell lines and primary cells[86]

PF-04449913

• Inhibited proliferation and induced cell death (minimally)

• Attenuated leukemia initiation potential in serial transplantation experiments

ALL cell lines[87, 88, 90]

Cyclopamine, saridegib (IPI-926)

• Decreased self-renewal as evidenced by decreased numbers of ALDH+ cells; significantly decreased secondary colony formation in vitro and leukemic engraftment in vivo[87]

Vismodegib

• Induced apoptotic cell death (reduced levels of p53 and cyclin D1)[90]

Sonidegib, BMS-833923

• Proliferation and apoptosis were not affected; data support hypothesis that Hh signaling may affect self-renewal[88]

MM CD138− tumor stem cells[91]

Cyclopamine

• Significantly inhibited cell growth relative to control

  1. ALDH aldehyde dehydrogenase, ALL acute lymphocytic leukemia, AML acute myeloid leukemia, CML chronic myeloid leukemia, LSC leukemic stem cell, MF myelofibrosis, MM multiple myeloma, SMO smoothened, TKI tyrosine kinase inhibitor.