title: Radiosensitization of renal cell carcinoma in vitro through the induction of autophagy.
abstract: OBJECTIVE
  For patients diagnosed with advanced renal cell carcinoma (RCC), there are few therapeutic options. Radiation therapy is predominantly used to treat metastasis and has not proven effective in the adjuvant setting for renal cancer. Furthermore, RCC is resistant to standard cytotoxic chemotherapies. Targeted anti-angiogenics are the standard of care for RCC but are not curative. Newer agents, such as mTOR inhibitors and others that induce autophagy, have shown great promise for treating RCC. Here, we investigate the potential use of the small molecule STF-62247 to modulate radiation.
  
  
  METHODS
  Using RCC cell lines, we evaluate sensitivity to radiation in addition to agents that induce autophagic cell death by clonogenic survival assays. Furthermore, these were also tested under physiological oxygen levels.
  
  
  RESULTS
  STF-62247 specifically induces autophagic cell death in cells that have lost VHL, an essential mutation in the development of RCC. Treatment with STF-62247 did not alter cell cycle progression but when combined with radiation increased cell killing under oxic and hypoxic/physiological conditions.
  
  
  CONCLUSIONS
  This study highlights the possibility of combining targeted therapeutics such as STF-62247 or temsirolimus with radiation to reduce the reliance on partial or full nephrectomy and improve patient prognosis.
authors.affiliation: The Cancer Research UK/MRC Gray Institute for Radiation Oncology and Biology, Department of Oncology, University of Oxford, UK.
authors.forename: Selvakumar
authors.initials: S
authors.lastname: Anbalagan
authors.forename: Isabel M
authors.initials: IM
authors.lastname: Pires
authors.forename: Christopher
authors.initials: C
authors.lastname: Blick
authors.forename: Mark A
authors.initials: MA
authors.lastname: Hill
authors.forename: David J P
authors.initials: DJ
authors.lastname: Ferguson
authors.forename: Denise A
authors.initials: DA
authors.lastname: Chan
authors.forename: Ester M
authors.initials: EM
authors.lastname: Hammond
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D001343:Autophagy / Q000187:drug effects; D002292:Carcinoma, Renal Cell / Q000235:genetics / Q000503:physiopathology / Q000532:radiotherapy*; D002453:Cell Cycle / Q000187:drug effects / Q000528:radiation effects; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000528:radiation effects; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics / Q000503:physiopathology / Q000532:radiotherapy*; D009154:Mutation; D011725:Pyridines / Q000494:pharmacology; D011829:Radiation Dosage; D011836:Radiation Tolerance / Q000502:physiology; D020123:Sirolimus / Q000031:analogs & derivatives / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology; D014410:Tumor Stem Cell Assay; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D011725:Pyridines; C530878:STF 62247; D013844:Thiazoles; C401859:temsirolimus; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C497446:VHL protein, human; D020123:Sirolimus