Pharmacodynamic and pharmacogenomic study of the nanoparticle conjugate of camptothecin CRLX101 for the treatment of cancer.
CRLX101 is a nanopharmaceutical consisting of cyclodextrin-based polymer molecule and camptothecin. The CRLX101 nanoparticle is designed to concentrate and slowly release camptothecin in tumors over an extended period of time. Tumor biopsy and blood samples collected from patients with advanced solid malignancies before and after CRLX101 treatment are subjected to immunohistochemistry and pharmacogenomics. The expression of Topoisomerase-1, Ki-67, CaIX, CD31 and VEGF decreased after CRLX101 treatment. The expressions of these proteins are inversely proportional with survival duration of the patients. The Drug Metabolism Enzymes and Transporters (DMET) array shows an allele frequency in patients similar to global populations with none of the SNPs associated with toxicity. The results suggest that the observed lower toxicity is not likely to be due to different genotypes in SNPs. CRLX101 demonstrates a promising anti-tumor activity in heavily pre-treated or treatment-refractory solid tumor malignancies presumably by inhibition of proliferation and angiogenesis correlating with tumor growth inhibition. From the clinical editor: In this cancer treatment study clinical samples collected from patients were subjected to immunohistochemistry and pharmacogenomics. The expressions of key proteins that are inversely proportional with survival duration of the patients decreased after treatment with CRLX101, a camptothecin slow-release nanoparticle conjugate. This anti-tumor activity in heavily pre-treated and treatment resistant solid tumors, promises a novel therapeutic approach.
Department of Molecular Pharmacology, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
Shikha
S
Gaur
Translational Research Laboratory, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
Yafan
Y
Wang
Department of Molecular Pharmacology, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
Leo
L
Kretzner
Translational Research Laboratory, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
Linling
L
Chen
Translational Research Laboratory, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
Terence
T
Yen
Bioinformatics Core Facility, Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
Xiwei
X
Wu
Bioinformatics Core Facility, Department of Molecular Medicine, Beckman Research Institute of the City of Hope, Duarte, CA, USA.
Yate-Ching
YC
Yuan
Chemical Engineering, California Institute of Technology, Pasadena, CA, USA.
Mark
M
Davis
Department of Molecular Pharmacology, Beckman Research Institute of the City of Hope, Duarte, CA, USA; Institute of Translational Medicine, Taipei Medical University, Taipei, Taiwan. Electronic address: yyen@coh.org.
Yun
Y
Yen
D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D001483:Base Sequence; D002166:Camptothecin / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D049109:Cell Proliferation / Q000187:drug effects; D003505:Cyclodextrins / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D016207:Cytokines / Q000097:blood; D017931:DNA Primers; D006801:Humans; D053758:Nanoparticles; D009369:Neoplasms / Q000188:drug therapy*; D009389:Neovascularization, Pathologic / Q000517:prevention & control; D010597:Pharmacogenetics; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction
D000970:Antineoplastic Agents; D003505:Cyclodextrins; D016207:Cytokines; D017931:DNA Primers; C542292:IT-101; D002166:Camptothecin
Camptothecin; HIF-1α; Immunohistochemistry; Nanoparticle; Polymer conjugate; Solid tumor; Topoisomerase 1