Novel and potent SHIP1 inhibitors for improving hematologic recovery following myelosuppressive therapies

ABSTRACT Despite recent advances in targeting cancer cellschemotherapy remains a mainstay of oncologyextending survival and providing cures for many types of cancerHoweverchemotherapy that ablates or suppresses bone marrow cells can be debilitating even when combined with autologous hematopoietic stem cell transplantationHSCTThe treatment causes severe side effects such as anemianeutropenia and thrombocytopeniathe consequences of which include hospitalizationtreatment delaysand dose reductions that compromise treatment efficacy and can even result in deathAlthough expensiverecombinant growth factors can assist with recovery from anemia and neutropeniahoweverthrombocytopenia remains an unmet medical needPlatelet transfusions provide temporary support but do not correct the underlying basis of thrombocytopeniawhich results from compromised stem progenitor functionAlterna has developed a novel technology called SHIPi that consists of the in vivo delivery of compounds that inhibit phosphatidylinositoltrisphosphatephosphataseSHIPa protein expressed in hematopoietic cellsSHIPnegatively regulates the proliferation of stem cellsinviting the hypothesis that inhibiting SHIPwould increase stem cell proliferation and survivalIndeedinvestigations of SHIPi have demonstrated that the technology can increase neutrophil numbers and also abrogate the growth of certain hematologic cancersMore recentlySHIPi was found to promote expansions of hematopoietic stem cells and mesenchymal stem cell compartmentsIt can also super induce the production of endogenous granulocyte colony stimulating factorG CSFthat acts on the hematopoietic stem progenitor cellHS PCcompartmentMoreoverSHIPi accelerates hematologic recovery after myelosuppressive radiation treatmentincluding the recovery neutrophils and plateletsThese inherent properties of SHIPi provide a mechanistic advantage over recombinant growth factors like G CSF and erythropoietin in promoting blood cell recoveryThe objective of this Phase I research project is to test and develop SHIPi approaches that will lead to improved hematologic recovery following chemotherapymyelosuppressive orablativecombined with HSCTSpecificallyafter synthesizing sufficient amounts of two highly active SHIPinhibitorsthe compoundsKKwill be characterized in vivo dose escalation and pharmacokinetic studies in rats to ensure that there will be appropriate exposure to the compounds in subsequent animal studiesNextthe compounds will be testedin vitrofor off target effectsAnd the final line of investigation will use a murine model of chemotherapy induced myelosupression to determine if the administration of SHIPinhibitors after chemotherapy enhances blood cell recoveryMice that receive chemotherapy and are treated using SHIPi are expected to show more rapid recovery of blood cell components compared to untreatednegativeand G CSF treatedpositivecontrols Narrative While chemotherapy is a mainstay in the treatment of cancersome types of chemotherapy deplete bone marrow cellsaffecting blood cell productionThe severely debilitating side effects frequently result in hospitalization and treatment delaysand may compel dose reductions that compromise drug efficacywith potentially fatal consequencesThis project will develop a novel technology to significantly improve blood cell recovery following chemotherapythus reducing healthcare costs for cancer patients and saving lives