Chemosensitizing Hypoxic Multiple Myeloma With Tunable, Long-Lived Oxygen Carriers

DESCRIPTION provided by applicant Hypoxia is a well characterized driver of solid tumor metastasis and recent clinical evidence in the blood cancer multiple myeloma MM has uncovered a major role for hypoxia in MM disease progression Patients with a more hypoxic MM phenotype exhibit substantially worse outcomes a phenomenon observed in a wide range of solid tumors In preclinical models of MM hypoxia increases with disease progression leading to up regulation of biomarkers e g SNAIL HIF a and CXCR associated with increased aggressiveness and dissemination of tumor cells Accordingly our preliminary measurements of hypoxia using an exogenous hypoxia biomarker pimonidazole have confirmed that essentially all MM cells in established bone marrow BM lesions are hypoxic Given that hypoxia can propel metastasis and increase resistance to chemotherapy in solid tumors and that hypoxia levels correlate with MM disease progression altering the hypoxic environment by delivering oxygen to the hypoxic tissue may improve MM disease progression and reduce treatment resistance We have engineered H NOX oxygen carrying proteins that are optimally designed for tumor penetration and have an excellent safety profile We therefore propose to use these long acting and safe H NOX oxygen carriers to suppress hypoxia in a disease model of MM in a manner that is not toxic to humans By oxygenating the hypoxic MM lesions this H NOX oxygen carrier is likely to delay or inhibit the biological changes that contribute to MM progression and may also sensitize MM cells to conventional chemotherapeutic treatments Omniox has engineered the H NOX oxygen binding protein variants specifically to release oxygen in hypoxic niches The initial effort funded by SBIR NCI Phase I II and IIB awards focused on developing OMX for the treatment of solid tumor hypoxia and enhancing radiation therapy Because OMX is designed to work over a period of hours it is not suitable for clinical indications requiring sustained tumor oxygenation such as MM To address this we have now engineered a second generation of H NOX oxygen carriers with longer circulation half lives h that maintain the ability to penetrate tumors and deliver oxygen over many weeks Here we propose to select an optimal H NOX candidate that effectively blunts hypoxia driven disease progression in mouse models of MM as a first step towards its clinical development In this proposal long lived H NOX oxygen carriers will be assessed for optimal hypoxia reduction in the BM niche of MM cells We are collaborating with UCSFandapos s MM Translation Initiative that was expressly established for this type of translational effort and has deep expertise in relevant MM disease models We will employ MM s and RPMI human cell models to recapitulate hallmarks of clinical MM including homing to the bone marrow osteolytic complications and eventual disease dissemination Once we select an effective H NOX variant in single dose Aim studies we will evaluate in Aim a week dosing regimen for its ability to alter the hypoxia mediated disseminating phenotype Finally in Aim using insights about hypoxia reduction effectiveness and its capacity to alter MM tumor cell phenotype we will combine H NOX with standard MM chemo and targeted therapies to evaluate chemosensitization and increase in efficacy A successful outcome of this Phase I project will lead to refined dosing strategies mechanism of action analyses and toxicological studies in support of IND filing and clinical development that will be outlined in a Phase II proposal PUBLIC HEALTH RELEVANCE Omniox has developed a class of long lived oxygen carrying protein products called H NOX that are tuned to release oxygen in hypoxic areas of tumors Hypoxia is emerging as a major feature of progressive multiple myeloma actively contributing to disease dissemination This project will test these long lived H NOX products for their potential to inhibit hypoxia driven disease progression as well as to enhance the efficacy of chemotherapy in late stage aggressive multiple myeloma