Phase II clinical trial of Hedgehog pathway inhibitor with low-dose cytarabine (Ara-C) extends the survival of acute myeloid leukemia (AML) patients

Acute myeloid leukemia (AML) accounts for >140,000 deaths globally per year with nearly ~10,600 deaths in the United States.  AML is the 2^nd most common adult leukemia with the 5-year overall survival rate of ~27% though it’s higher (60-70%) for children.  AML is caused by myeloid cells forming leukemic blasts instead of undergoing normal differentiation.  The rapid accumulation of abnormal cells in bone marrow with the resultant deficiency in red blood cells, platelets or certain white blood cells negatively affects immune and other physiological functions.  The current efforts to manage AML include chemotherapy, hematopoietic stem cell transplantation and tyrosine kinase inhibitors.

The malignancy in AML is attributed to the acquiring of genetic mutations that arrest cell differentiation and cause uncontrolled proliferation.  The block in differentiation, which may occur at distinct stages, arrests hematopoietic stem cells as myeloid stem cells or myeloid blasts instead of developing into monocytes or granulocytes.  A number of chromosomal rearrangements (e.g. translocation, inversion) have been documented in AML and the resultant gene product may affect tumor progression.  In the case of acute promyelocytic leukemia (a subtype of AML), translocation t(15;17) encodes the fusion protein PML-RARα, which transcriptionally regulates the genes inhibiting myeloid differentiation (Melnick et al., 1999).

For older AML patients, fewer treatment options are available as they are ineligible for intensive chemotherapy, opting for less aggressive treatment, i.e. low-dose cytarabine [also known as aracytidine or cytosine arabinoside (Ara-C)] or hypomethylating agents.  Administering the hypomethylating agent decitabine (5-aza-2'-deoxycytidine), however, only slightly extended the median overall survival (Kantarjian et al., 2012).  Thus, new therapies are needed to improve their survival.

The Hedgehog signaling pathway plays a key role in embryonic development.   Hedgehog (HH) gene was originally discovered while studying the genetic mutants affecting the anterior-posterior body axis of Drosophila by Nüsslein-Volhard and colleagues (Nobel prize, 1995).  The HH protein defines the antero-posterior orientation of the Drosophila embryo and its mutants display abnormally short and stubby larvae (Lee et al., 1992).  In vertebrates, the HH homologue, Secreted Sonic Hedgehog (SHH) protein, binds to Patched-1 (PTCH1) receptor of the target cells and blocks it from inhibiting the downstream protein Smoothened (SMO).  This leads to the activation of GLI transcription factors to regulate the transcription of Hedgehog-target genes.

Intriguingly, the hedgehog signaling pathway is activated in basal cell carcinoma as well as the cancers of the breast, brain and prostate (Sari et al., 2018).  The uncontrolled activation of the signaling pathway may contribute to the persistence of cancer stem cells exhibiting drug resistance.  In myeloid leukemic cells, inhibiting the HH signaling reduced P-glycoprotein associated with multi-drug resistance, suggesting that activation of the HH pathway may confer resistance to chemotherapy (Queiroz et al, 2010).

To pharmacologically abrogate the Hedgehog signaling pathway, Glasdegib was developed by Pfizer Inc., which inhibits SMO protein (Munchhof et al., 2011).  Pre-clinical studies demonstrated that Glasdegib suppresses the growth of AML cells and sensitizes chemotherapy-resistant AML cells to cytarabine (Fukushima et al, 2016).  These results inspired several clinical trials.  Recently, a Phase II clinical study was conducted at the M. D. Anderson Cancer Center and other medical centers to examine the therapeutic efficacy of Glasdegib and low-dose cytarabine in newly diagnosed AML patients (Cortes et al., 2019).  It showed that the combined regimen extends overall survival (~4 months), which led to its approval by FDA for the treatment of newly diagnosed older AML patients, who cannot receive intensive chemotherapy.   Sonidegib is another inhibitor of SMO developed by Novartis, Inc.

Bio-Synthesis, Inc. provides extensive options for the application of various modified nucleosides for research or therapy purposes.  It specializes in oligonucleotide modification and provides an extensive array of chemically modified nucleoside analogues (over ~200).  For instance, with Ara-C, we offer oligonucleotide modification to selectively conjugate to DNA binding proteins to study their interaction.   For bridged nucleic acid (BNA), it has recently acquired a license from BNA Inc. of Osaka, Japan, for the manufacturing and distribution of BNA^NC, a third generation of BNA oligonucleotides.  Bio-Synthesis, Inc. has recently entered into collaborative agreement with Bind Therapeutics, Inc. to synthesize miR-21 blocker using BNA.  The BNA technology that we offer provides superior, unequalled advantages in base stacking, binding affinity, aqueous solubility and nuclease resistance.  More importantly, BNA oligonucleotide exhibits lesser toxicity than other modified nucleotides for clinical application.

https://www.biosyn.com/oligonucleotideproduct/aracytidine-ara-c-oligonucleotide-modification.aspx#!

References

Cortes JE, et al.  Randomized comparison of low dose cytarabine with or without glasdegib in patients with newly diagnosed acute myeloid leukemia or high-risk myelodysplastic syndrome. (2019)  Leukemia 33:379-389.  PMID: 30555165  doi: 10.1038/s41375-018-0312-9. Epub 2018 Dec 16. 

Fukushima N, et al.  Small-molecule Hedgehog inhibitor attenuates the leukemia-initiation potential of acute myeloid leukemia cells. (2016) Cancer Sci  107:1422-1429.  PMID: 27461445  doi: 10.1111/cas.13019

Kantarjian HM, et al.  Multicenter, randomized, open-label, phase III trial of decitabine versus patient choice, with physician advice, of either supportive care or low-dose cytarabine for the treatment of older patients with newly diagnosed acute myeloid leukemia. (2012)  J Clin Oncol 30:2670-7.  PMID: 22689805

Lee JJ, von Kessler DP, Parks S, Beachy PA.  Secretion and localized transcription suggest a role in positional signaling for products of the segmentation gene hedgehog. (1992) Cell 71:33-50. PMID: 1394430 DOI: 10.1016/0092-8674(92)90264-d

Melnick A, Licht JD. Deconstructing a disease: RARalpha, its fusion partners, and their roles in the pathogenesis of acute promyelocytic leukemia. (1999)  Blood  93:3167-215. PMID: 10233871

Munchhof MJ, et al.  Discovery of PF-04449913, a Potent and Orally Bioavailable Inhibitor of Smoothened.  (2011)  ACS Med Chem Lett 3:106-11.  PMID: 24900436  doi: 10.1021/ml2002423. eCollection

Queiroz KC, et al. Hedgehog signaling maintains chemoresistance in myeloid leukemic cells. (2010)  Oncogene  29:6314-22.   PMID: 20802532   DOI: 10.1038/onc.2010.375

Sari IN, Phi LTH, Jun N, Wijaya YT, Lee S, Kwon HY.  Hedgehog Signaling in Cancer: A Prospective Therapeutic Target for Eradicating Cancer Stem Cells.  (2018)  Cells 7(11). pii: E208.   PMID: 30423843   doi: 10.3390/cells7110208