Niamh Keane

Targeting the Pim kinases in multiple myeloma.

Multiple myeloma (MM) is a plasma cell malignancy that remains incurable. Novel treatment strategies to improve survival are urgently required. The Pims are a small family of serine/threonine kinases with increased expression across the hematological malignancies. Pim-2 shows highest expression in MM and constitutes a promising therapeutic target. It is upregulated by the bone marrow microenvironment to mediate proliferation and promote MM survival. Pim-2 also has a key role in the bone destruction typically seen in MM. Additional putative roles of the Pim kinases in MM include trafficking of malignant cells, promoting oncogenic signaling in the hypoxic bone marrow microenvironment and mediating resistance to therapy. A number of Pim inhibitors are now under development with lead compounds entering the clinic. The ATP-competitive Pim inhibitor LGH447 has recently been reported to have single agent activity in MM. It is anticipated that Pim inhibition will be of clinical benefit in combination with standard treatments and/or with novel drugs targeting other survival pathways in MM.

EPHA3 as a novel therapeutic target in the hematological malignancies

The Eph receptors are the largest family of tyrosine kinases and are of increasing interest in developmental therapeutics. Their unique method of interaction with their ligands, the ephrins, via bidirectional signaling, and their variable expression in different tissues are well documented. Ephs are upregulated in, and critical to, embryological processes, most notably development of the neurological system. They are central in many processes involving cell motility and adhesion. Recent findings on elevated expression of Eph receptors in human malignancies as well as in stem cell environments are of particular interest. With increasing focus on molecularly targeted anticancer therapies, exploration of the potential of Eph receptors as therapeutic targets in both solid and hematologic malignancies has begun. The most promising of the Eph receptors in this regard is EPHA3, which is overexpressed in many hematologic malignancies. Preclinical data support the value of pursuing this target for further development, and lead compounds are now entering the clinic.

Vosaroxin: a new valuable tool with the potential to replace anthracyclines in the treatment of AML?

Introduction: Despite significant advances in diagnosis and supportive care, the majority of patients diagnosed with acute myeloid leukemia (AML) ultimately die of their disease. Standard intensive induction treatment continues to comprise cytarabine and a topoisomerase II (topo II) poison, usually an anthracycline. Vosaroxin, a novel first-in-class quinolone derivative has been developed for use in the treatment of AML as a new-generation topo II inhibitor. It has shown promising activity as a monotherapy and also in combination with intermediate dose cytarabine (IDAC) in relapsed and refractory patient cohorts with minimal toxicity and good tolerability. Areas covered: The authors discuss the mechanism of action of vosaroxin, the pharmacokinetics, safety and tolerability, preclinical and clinical trial results available as well as areas of ongoing research. Expert opinion: Vosaroxin has shown efficacy as a novel cytotoxic agent, and despite a similar mechanism of action has significant advantages over anthracyclines. It evades common resistance pathways of p53 and P-glycoprotein (P- gp) and does not appear to generate significant reactive oxygen species (ROS) associated with these agents. Should future investigation confirm its efficacy and advantageous safety profile, vosaroxin could potentially replace older generation topoisomerase poisons in the treatment of AML and other malignant conditions.

AKT as a therapeutic target in multiple myeloma

Introduction: Multiple myeloma remains an incurable malignancy with poor survival. Novel therapeutic approaches capable of improving outcomes in patients with multiple myeloma are urgently required. AKT is a central node in the phosphatidylinositol-3-kinase/AKT/mammalian target of rapamycin signaling pathway with high expression in advanced and resistant multiple myeloma. AKT contributes to multiple oncogenic functions in multiple myeloma which may be exploited therapeutically. Promising preclinical data has lent support for pursuing further development of AKT inhibitors in multiple myeloma. Lead drugs are now entering the clinic. Areas covered: The rationale for AKT inhibition in multiple myeloma, pharmacological subtypes of AKT inhibitors in development, available results of clinical studies of AKT inhibitors and suitable drug partners for further development in combination with AKT inhibition in multiple myeloma are discussed. Expert opinion: AKT inhibitors are a welcome addition to the armamentarium against multiple myeloma and promising clinical activity is being reported from ongoing trials in combination with established and/or novel treatment approaches. AKT inhibitors may be set to improve patient outcomes when used in combination with synergistic drug partners.

Elacytarabine: lipid vector technology under investigation in acute myeloid leukemia.

Cytosine arabinoside (cytarabine or Ara-C) has been one of the cornerstones of treatment of acute myeloid leukemia since its approval in 1969. Standard induction therapy worldwide for all patients deemed fit for treatment (excluding those with acute promyelocytic leukemia) remains unchanged for over 40 years and consists of Ara-C administered by continuous infusion in combination with a topoisomerase II inhibitor (e.g., daunorubicin, idarubicin and mitoxantrone). Despite decades of clinical investigation, the optimum dose of both agents still remains unclear. Although higher doses of Ara-C have been shown to improve response rates, the elderly poorly tolerate these regimens. Resistance mechanisms also develop or may be present at diagnosis resulting in poor outcomes. Elacytarabine (CP-4055), an elaidic acid ester of Ara-C, has been developed using lipid vector technology in an attempt to overcome these limitations. Clinical data are encouraging, with evidence suggesting that this novel agent is circumventing resistance mechanisms but retaining the potent antileukemic efficacy of Ara-C.

Perifosine – a new option in treatment of acute myeloid leukemia?

Introduction: Perifosine is a novel targeted oral Akt inhibitor. In preclinical leukemia models, perifosine has an independent cytotoxic potential but also synergizes well with other rationally selected targeted agents. The evidence from clinical trials supporting the use of perifosine in the therapy of leukemias is limited. The optimal dose and schedule have yet to be defined. However, given its favorable toxicity profile and mechanism of action, the therapeutic potential of perifosine should be evaluated in well-designed clinical trials. Areas covered: The role of the phosphatidylinositol-3 kinase (PI3K)/Akt zpathway in normal cells, cancer and leukemias is discussed. The mechanism of action of perifosine and the basic information on the development and chemical properties are summarized. The evidence from in vivo and in vitro studies is presented. The efficacy and side effect profile are summarized. Expert opinion: The safety and tolerability profile of perifosine are satisfactory. The evidence from clinical trials in patients with leukemias is very limited. The preclinical data are encouraging. Perifosine has the potential to play a role in the treatment of leukemias in the future. Its role needs to be confirmed in clinical trials.

5-Azacytidine for the treatment of myelodysplastic syndromes

Introduction: 5-Azacytidine is a pyrimidine nucleoside analog of cytidine that undergoes incorporation into DNA and blocks DNA methyltransferase leading to hypomethylation and potentially beneficial re-expression of abnormally silenced genes. It is the first agent approved for use in patients with myelodysplastic syndromes (MDSs) based on its improvement in overall survival as monotherapy. Evidence of efficacy in combination with other agents is also accumulating. Areas covered: Key information on mechanisms of action is presented. Development, synthesis, and pharmacokinetics are also outlined. Key safety, tolerability, and efficacy data from clinical trials of 5-azacytidine as monotherapy as well as in combination are also presented. Expert opinion: Our understanding of the molecular basis and pathogenesis of MDS continues to evolve rapidly. 5-Azacytidine has been shown to improve both overall survival and quality of life in patients with high-risk MDS. Currently, the oral route of administration is undergoing evaluation in clinical trials. Used as a monotherapy and also in novel combinations, 5-azacytidine has the potential to further improve the prognosis of some patients with MDS.

E-selectin ligands recognised by HECA452 induce drug resistance in myeloma, which is overcome by the E-selectin antagonist, GMI-1271

Multiple myeloma (MM) is characterized by the clonal expansion and metastatic spread of malignant plasma cells to multiple sites in the bone marrow (BM). Recently, we implicated the sialyltransferase ST3Gal-6, an enzyme critical to the generation of E-selectin ligands, in MM BM homing and resistance to therapy. Since E-selectin is constitutively expressed in the BM microvasculature, we wished to establish the contribution of E-selectin ligands to MM biology. We report that functional E-selectin ligands are restricted to a minor subpopulation of MM cell lines which, upon expansion, demonstrate specific and robust interaction with recombinant E-selectin in vitro. Moreover, an increase in the mRNA levels of genes involved in the generation of E-selectin ligands was associated with inferior progression-free survival in the CoMMpass study. In vivo, E-selectin ligand-enriched cells induced a more aggressive disease and were completely insensitive to Bortezomib. Importantly, this resistance could be reverted by co-administration of GMI-1271, a specific glycomimetic antagonist of E-selectin. Finally, we report that E-selectin ligand-bearing cells are present in primary MM samples from BM and peripheral blood with a higher proportion seen in relapsed patients. This study provides a rationale for targeting E-selectin receptor/ligand interactions to overcome MM metastasis and chemoresistance.