*1.4.1 Smoothened inhibitors*

The Hedgehog (Hh) family of proteins control cell growth and survival. The Hedgehog signalling pathway (HhP) is essential for embryonic development and usually silenced in adult tissues. Germline mutations that subtly affect Hh pathway activity are associated with developmental disorders, whereas somatic mutations activating the pathway have been linked to multiple forms of human

cancer [81–83]. Aberrant activation of the HhP has been implicated in the maintenance of leukaemia stem cells in several model systems. Overexpression of various HH/GLI components have been found in chemotherapy resistant myeloid blasts and subsequent inhibition of the HH/GLI pathway revised the sensitivity to chemotherapy [84, 85].

#### *1.4.1.1 Glasdegib*

Glasdegib (PF-913) is an oral, potent, selective, small molecule inhibitor of HH/GLI signalling, which binds to the smoothened (SMO) receptor [86]. In vitro treatment with Glasdegib induced a decrease in the quiescent cell population and in vivo treatment attenuated the leukemia-initiation potential of AML cells in a serial transplantation mouse model [87]. An open-label, dose-finding, phase 1 study of glasdegib in 47 adult patients with myeloid malignancies (AML, n = 28) found 400 mg once daily as the MTD and a minor response was achieved (over 25% decrease from baseline in BM blasts) or better in more than 30% of AML patients. The most common treatment-related adverse events included dysgeusia, decreased appetite, and alopecia [88]. Based on this study a phase II, randomized, open-label, multicenter study evaluated the efficacy of glasdegib plus low-dose cytarabine (LDAC) in patients with AML or high-risk myelodysplastic syndrome unsuitable for intensive chemotherapy. Glasdegib 100 mg was administered orally in 28-day cycles. Eighty-eight and 44 patients were randomized to glasdegib/LDAC and LDAC, respectively. Median overall survival was 8.8 (6.9–9.9) months with glasdegib/LDAC and 4.9 (3.5–6.0) months with LDAC. Fifteen (17.0%) and 1 (2.3%) patients in the glasdegib/LDAC and LDAC arms, respectively, achieved complete remission (P < 0.05) [89]. Based on this study the FDA approved glasdegib in combination with low dose cytarabine for AML patients unfit for IC. Another phase-II study to evaluate glasdegib from day 3 plus standard-induction chemotherapy for untreated and fit AML or high-risk MDS patients revealed that 46.4% of patients achieved CR. Among all 69 patients, median OS was 14.9 (80% CI 13.4–19.3) months, with 12-month survival probability 66.6%. The most common treatment-related adverse events (≥50% patients) were diarrhea and nausea [90].

#### *1.4.1.2 Sonidegib*

Sonidegib (LDE225) is a specific SMO inhibitor and in refractory AML cells increased cell apoptosis and the efficacy of Adriamycin against tumor cells and lowered the expression of the targeted protein [91]. In a phase I/Ib study of azacitidine and sonidegib in myeloid malignancies the best response outcome for untreated AML/MDS patients was 23.1% and for rel/ref 7.1%. However, the rate of SD was remarkably high particularly in the rel/ref AML population at 76%. The most common Gr 3/4 AEs were: thrombocytopenia, neutropenia, anemia and leukopenia [92].

#### *1.4.1.3 Vismodegib*

Vismodegib (GDC-0449) safety and efficacy were evaluated in a phase Ib trial in patients with relapsed/refractory acute myeloid leukaemia. All enrolled patients had received prior cancer therapy; most had received more than one therapy, including hypomethylating agents, immunomodulators and targeted signalling pathway inhibitors. 38 received at least one dose of vismodegib but the study was terminated by the sponsor because of lack of efficacy [93].

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*Target Therapy in Acute Myeloid Leukemia DOI: http://dx.doi.org/10.5772/intechopen.94422*

Polo-like kinases (Plks) are a family of 5 highly conserved serine/threonine protein kinases. They play a key role in mitotic checkpoint regulation and cell division. Plk1 has been shown to be overexpressed in a range of human cancers, including non-small cell lung cancer, prostate, ovarian, breast, and colorectal cancer as well

Volasertib (BI 6727) is a low-molecular-weight, adenosine triphosphate–competitive kinase inhibitor that potently inhibits Plk1 [97]. In a randomized, phase 1/2, open-label, multicenter trial of low-dose cytarabine with or without volasertib in patients with AML ineligible for intensive induction therapy eighty-seven patients (median age 75 years) received LDAC or LDAC + volasertib. The result confirmed greater clinical efficacy in the combination arm, statistically significant in CR (30 vs. 13.3%, P = 0.052). Median overall survival was 8.0 vs. 5.2 months, respectively. LDAC + volasertib led to an increased frequency of adverse events that was most pronounced for neutropenic fever/infections and gastrointestinal events [98].

The endothelial cell adhesion molecule E-selectin is a key component of the bone marrow hematopoietic stem cell (HSC) vascular niche regulating balance between HSC self-renewal and commitment. E-selectin is expressed transiently in the normal vasculature during an inflammatory response and constitutively in the bone marrow. E-selectin directly triggers signaling pathways that promote malignant cell survival and regeneration. In vivo AML blasts with highest E-selectin binding potential are 12-fold more likely to survive chemotherapy and main contributors to

Uproleselan (GMI-1271) is a novel antagonist of E-selectin that down-regulates cell survival pathways and enhances chemotherapy response. In a single arm phase I/II trial of 47 adults with relapsed/refractory AML were treated with GMI-1271 in combination with MEC chemotherapy. GMI-1271 was given 24 hrs prior, then every 12 hrs during and for 48 hrs post induction/consolidation. With a median follow-up of 11 months, the ph 1 median leukemia free survival was not reached and overall survival was 7.6 months. ORR (CR/CRi/MLFS/PR) was evaluable in 21 patients was 50%. Remission rate (CR/CRi) was 45%.Common Gr 3/4 AEs were febrile neutropenia, sepsis, bacteremia, hypoxia. 30 and 60 day mortality were 0 and 7%, respectively [101]. A pivotal phase 2/3 study (NCT03616470) is underway to assess the efficacy and safety of uproleselan with standard salvage chemotherapy in R/R AML. The study is a global, randomized, double-blind, phase 3 trial in adults aged

The development of immune checkpoint inhibitors (ICIs) is a revolutionary milestone in the field of immuno-oncology. Immune checkpoint blockade removes inhibitory signals of T-cell activation, which enables tumor-reactive T cells to overcome regulatory mechanisms and mount an effective antitumor response [103–105].

18–75 years with R/R AML and fit for chemotherapy [102].

**1.5 Polo-like kinase inhibitors**

as AML [94–96].

**1.6 E-selectin inhibitors**

disease relapse [99, 100].

**1.7 Checkpoint inhibitors**

*1.6.1 Uproleselan*

*1.5.1 Volasertib*
