Phase I trial of induction histone deacetylase and proteasome inhibition followed by surgery in non-small-cell lung cancer.
BACKGROUND
Despite complete surgical resection survival in early-stage non-small-cell lung cancer (NSCLC) remains poor. On the basis of prior preclinical evaluations, we hypothesized that combined induction proteasome and histone deacetylase inhibitor therapy, followed by tumor resection, is feasible.


METHODS
A phase I clinical trial using a two-staged multiple-agent design of bortezomib and vorinostat as induction therapy followed by consolidative surgery in patients with NSCLC was performed. Standard toxicity and maximum tolerated dose were examined. Pre- and post-treatment tumor gene-expression arrays were performed and analyzed. Pre- and post-treatment fluorodeoxyglucose-positron emission tomography imaging was used to assess tumor metabolism. Finally, serum 20S proteasome levels were analyzed with enzyme-linked immunosorbent assay, and selected intratumoral proteins were assessed by immunohistochemistry.


RESULTS
Of the 34-four patients providing written consent to participate in the trial, 21 were enrolled. One patient withdrew early because of disease progression. The maximum tolerated dose was bortezomib 1.3 mg/m and vorinostat 300 mg twice daily. There were grade III dose-limiting toxicities of fatigue and hypophosphatemia, which were self-limited. There was no mortality. Thirty percent of patients (6 of 20) had more than 60% histologic necrosis of their tumor after treatment, with two having 90% or more tumor necrosis. Tumor metabolism, 20S proteasome activity, and specific protein expression did not demonstrate consistent results. Gene-expression arrays comparing pre- and post-therapy NSCLC specimens revealed robust intratumoral changes in specific genes.


CONCLUSIONS
Induction bortezomib and vorinostat therapy followed by surgery in patients with operable NSCLC is feasible. Correlative gene-expression studies suggest new targets and cell-signaling pathways that may be important in modulating this combined therapy.
Department of Surgery, University of Virginia, Charlottesville, VA, USA. djones@virginia.edu
David R
DR
Jones
Christopher A
CA
Moskaluk
Heidi H
HH
Gillenwater
Gina R
GR
Petroni
Sandra G
SG
Burks
Jennifer
J
Philips
Patrice K
PK
Rehm
Juan
J
Olazagasti
Benjamin D
BD
Kozower
Yongde
Y
Bao
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D000368:Aged; D000369:Aged, 80 and over; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D001897:Boronic Acids / Q000008:administration & dosage; D000069286:Bortezomib; D018287:Carcinoma, Large Cell / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D003131:Combined Modality Therapy; D005260:Female; D005500:Follow-Up Studies; D020869:Gene Expression Profiling; D006655:Histone Deacetylases / Q000737:chemistry*; D006801:Humans; D006877:Hydroxamic Acids / Q000008:administration & dosage; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000601:surgery; D008297:Male; D020714:Maximum Tolerated Dose; D008875:Middle Aged; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D011379:Prognosis; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry*; D011719:Pyrazines / Q000008:administration & dosage; D000077337:Vorinostat
D014408:Biomarkers, Tumor; D001897:Boronic Acids; D006877:Hydroxamic Acids; D011719:Pyrazines; D000077337:Vorinostat; D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex; D006655:Histone Deacetylases