Myelofibrosis
Current treatment strategies
Unmet need in the treatment of MF
Rationale for targeting the Hh pathway in MF
The Hh pathway and its role in hematopoiesis
Preclinical model | Evidence | |
---|---|---|
Activated Hh signaling
| • Ptch mutant chimeric explant cultures | • Hh signaling from ventral tissues surrounding the AGM was shown to induce and increase HSC activity in a time-dependent manner[64] |
• Ptch+/− mice vs wild-type mice (bone marrow, fetal liver cells) | ||
• Conditional loss of Ptch in adult murine HSCs | • Ptch deletion in HSCs did not cause Hh pathway activation or affect hematopoiesis[67] | |
• Conditional loss of Ptch in adult murine non-HSCs | ||
• Ptch deletion in non-HSCs led to aberrant hematopoiesis, including apoptosis of lymphoid progenitors in epithelial cells, increased numbers of lineage-negative bone marrow cells, and increased mobilization of myeloid progenitors in bone marrow niche cells[67] | ||
Impaired Hh signaling
| • Ihh−/− knockout mice | • Terminal erythroid differentiation was defective despite normal production of HSCs and progenitor cells[62] |
• Dhh- deficient mouse model | • Dhh was shown to regulate normal and stress-induced erythropoiesis by preventing erythropoiesis differentiation in the spleen and bone marrow[71] | |
• Conditional deletion of Smo in fetal and adult hematopoietic and endothelial cells (Vav driven Cre-Lox system) | • Decreased stem cell activity was observed despite normal number and differentiation of HSCs[68] | |
• Smo- depleted mouse stromal cells | • Differentiation of hematopoietic progenitors was impaired—the number of myeloid progenitors was increased at the expense of lymphoid progenitors[72] | |
• Caused reduced expression of factors involved in B-cell development or osteoblast differentiation | ||
• Gli1
null
mice | • Decreased proliferation of long-term HSCs and myeloid progenitors, reduced myeloid differentiation, and delayed recovery following 5-FU treatment were observed[69] | |
• Human pluripotent stem cells | • Gli3
R
, the repressor form of Gli3, was shown to be necessary and sufficient in the initiation and regulation of adult hematopoietic specification[70] |
The Hh pathway in MF 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 |
Cyclopamine | • Reduced LSC numbers and secondary transplantation capacity in BCR-ABL+ cells | |
Vismodegib (GDC-0449), sonidegib | • Inhibited cell growth, self-renewal, and serial transplantation | |
• Enhanced activity of BCR-ABL–targeted TKIs | ||
AML cell lines and primary cells[86] | PF-04449913 | • Inhibited proliferation and induced cell death (minimally) |
• Attenuated leukemia initiation potential in serial transplantation experiments | ||
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 |
Clinical studies of HH pathway inhibitors in patients with MF and other hematologic malignancies
Smo inhibitor | Patient population | Phase | Combination partner | Primary endpoint | Statusa | ClinicalTrials.gov identifier |
---|---|---|---|---|---|---|
Sonidegib (LDE225) | PMF, post-PV MF, post-ET MF | 1/2 | Ruxolitinib | DLTs, MTD and/or RP2D (of combination), proportion of patients achieving ≥ 35% decrease in spleen volume | Recruiting | NCT01787552 |
Acute leukemias | 2 | CR, CRi | Recruiting | NCT01826214 | ||
CML | 1 | Nilotinib | DLT, MTD, RP2D | Recruiting | NCT01456676 | |
PF-04449913 | Refractory, resistant, or intolerant select hematologic malignancies | 1 | DLT | Completed | NCT00953758[109] | |
AML/MDS | 1/2 | Chemotherapy | DLT, CRR, OS | Recruiting | NCT01546038 | |
Acute leukemias | 2 | Post–stem cell transplant | Relapse-free survival | Recruiting | NCT01841333 | |
MDS | 2 | ORR | Recruiting | NCT01842646 | ||
Vismodegib (GDC-0449) | AML/MDS | 1b/2 | ORR | Recruiting | NCT01880437 | |
Lymphomas (B cell, CLL) | 2 | ORR | Recruiting | NCT01944943 | ||
MM | 1 | Post–stem cell transplant | Change in MM CSC counts | Ongoing, not recruiting | NCT01330173 | |
BMS-833923 | CML | 1/2 | Dasatinib | RP2D for combination | Completed | NCT01218477 |
2 | Dasatinib | MMR | Ongoing, not recruiting | NCT01357655[89] | ||
MM | 1 | Lenalidomide + dexamethasone or bortezomib | DLT, MTD, RP2D | Completed | NCT00884546[110] |