title: XPO1 Inhibition Enhances Radiation Response in Preclinical Models of Rectal Cancer.
abstract: OBJECTIVE
  Combination of radiation with radiosensitizing chemotherapeutic agents improves outcomes for locally advanced rectal cancer. Current treatment includes 5-fluorouracil-based chemoradiation prior to surgical resection; however pathologic complete response varies from 15% to 20%, prompting the need to identify new radiosensitizers. Exportin 1 (XPO1, also known as chromosome region 1, CRM1) mediates the nuclear export of critical proteins required for rectal cancer proliferation and treatment resistance. We hypothesize that inhibition of XPO1 may radiosensitize cancer cells by altering the function of these critical proteins resulting in decreased radiation resistance and enhanced antitumoral effects.
  
  
  METHODS
  To test our hypothesis, we used the selective XPO1 inhibitor, selinexor, to inhibit nuclear export in combination with radiation fractions similar to that given in clinical practice for rectal cancer: hypofractionated short-course radiation dosage of 5 Gy per fraction or the conventional long-course radiation dosage of 1 Gy fractions. Single and combination treatments were tested in colorectal cancer cell lines and xenograft tumor models.
  
  
  RESULTS
  Combination treatment of radiotherapy and selinexor resulted in an increase of apoptosis and decrease of proliferation compared with single treatment, which correlated with reduced tumor size. We found that the combination promoted nuclear survivin accumulation and subsequent depletion, resulting in increased apoptosis and enhanced radiation antitumoral effects.
  
  
  CONCLUSIONS
  Our findings suggest a novel therapeutic option for improving radiation sensitivity in the setting of rectal cancer and provide the scientific rationale to evaluate this combination strategy for clinical trials.
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. jcusack@partners.org isabel.ferreironeira@gmail.com.
authors.forename: Isabel
authors.initials: I
authors.lastname: Ferreiro-Neira
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Nancy E
authors.initials: NE
authors.lastname: Torres
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Lukas F
authors.initials: LF
authors.lastname: Liesenfeld
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Carlos H F
authors.initials: CH
authors.lastname: Chan
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts.
authors.forename: Tristan
authors.initials: T
authors.lastname: Penson
authors.affiliation: Karyopharm Therapeutics, Natick, Massachusetts.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Landesman
authors.affiliation: Karyopharm Therapeutics, Natick, Massachusetts.
authors.forename: William
authors.initials: W
authors.lastname: Senapedis
authors.affiliation: Karyopharm Therapeutics, Natick, Massachusetts.
authors.forename: Sharon
authors.initials: S
authors.lastname: Shacham
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts. Department of Radiation Oncology, Massachusetts General Hospital, Boston, Massachusetts.
authors.forename: Theodore S
authors.initials: TS
authors.lastname: Hong
authors.affiliation: Division of Surgical Oncology, Massachusetts General Hospital, Boston, Massachusetts. Harvard Medical School, Boston, Massachusetts. jcusack@partners.org isabel.ferreironeira@gmail.com.
authors.forename: James C
authors.initials: JC
authors.lastname: Cusack
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000528:radiation effects; D045744:Cell Line, Tumor; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology; D051034:Inhibitor of Apoptosis Proteins / Q000378:metabolism; D028884:Karyopherins / Q000037:antagonists & inhibitors*; D051379:Mice; D011827:Radiation; D011836:Radiation Tolerance / Q000187:drug effects*; D011838:Radiation-Sensitizing Agents / Q000494:pharmacology; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors*; D012004:Rectal Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000532:radiotherapy; D014230:Triazoles / Q000494:pharmacology; D047368:Tumor Burden / Q000187:drug effects / Q000528:radiation effects; D023041:Xenograft Model Antitumor Assays; D000097606:Exportin 1 Protein
chemical_list: D006834:Hydrazines; D051034:Inhibitor of Apoptosis Proteins; D028884:Karyopherins; D011838:Radiation-Sensitizing Agents; D018160:Receptors, Cytoplasmic and Nuclear; D014230:Triazoles; D000097606:Exportin 1 Protein; C585161:selinexor