Targeting DNA damage response pathways for the treatment of advanced lung cancer

ABSTRACTThere is an urgentunmet need for novel therapeutic approaches that are efficacious against lung cancerRanking first among cancer deaths in the U Sthis disease hasyear relative survival rates of andltMost lung cancers are non small cellNSCLCof casesCurative surgery is not an option for theof NSCLC patients who present with advanced stage III cancerFor these patients chemo radiation therapy remains the standard of careand presently there is no effective strategy to improve radiation therapy outcomesThe central innovative theme of this proposal is that the novel chemical entity YTRinhibits recruitment of pTNPMnucleophosminphosphorylated at threonineto DNA double strand breaksDSBsthereby improving tumor response to radiationFailure to recruit pTNPMto DSB repair foci significantly impairs DSB repair and increases radiation induced tumor cell deathImportantly we have shown that YTRpreferentially impairs pTNPMfunction in tumor cellscompared to normal cellsWe successfully completed all PhaseSTTRRmilestonesWe developed a sensitive bioanalytical method to quantitate YTRconcentrations in mouse plasmaWe showed thatnM YTRinhibits repair of DNA DSBs in irradiated tumor cells and significantly increases radiation cytotoxicity in seven genetically distinct NSCLC cell linesIn an Axenograft mouse modelintraperitonealIPinjection of YTRfollowed by tumor irradiationq d xincreased the survival of tumor bearing miceof mice treated with YTRGy were alivedays after treatment whereas onlyof mice treated with placeboGy liveddays post treatmentWe developed an intravenousIVYTRformulation suitable for use in miceWe measurednM YTRin plasma after a single IV dosea level matching that measured after an efficacious IP doseandnM YTRin plasma at the end of aday IV dosing regimenThe goals for our collaborative SBIR Phaseresearch program at Cumberland Pharmaceuticals Incand Vanderbilt University Medical Center are todemonstrate that systemic exposure to YTRafter IV administration results in dosedependent therapeutic benefitmeasured as increased tumor response to radiation and increased survival of tumor bearing miceanddemonstrate that the IV drug product intended for human use is of acceptable qualityis suitable to deliver a therapeutic human dose of YTRand supports a future New Investigative Drug application for YTROur ultimate product is a safe and effective IV YTRdrug product intended for use in conjunction with NSCLC patientsandaposchemo radiotherapy regimens to effectively control primary tumor growthwithout promoting normal tissue damagean outcome not achieved by the current standard of care therapy NARRATIVELung cancer patients diagnosed as having non small cell lung cancers have very pooryear survival ratesandltand fail to benefit from newer targeted therapies used for treating other types of lung cancersFor nonsmall cell lung cancersradiation therapy remains a cornerstone of the standard of careThis research aims to develop a safe and effective drug that renders tumor cells more susceptible to the toxic effects of therapeutic ionizing radiationthereby decreasing tumor growth and increasing patient survivalwith less damage to surrounding normal tissues