2. Academic Validation
  3. A novel strategy for combination of clofarabine and pictilisib is synergistic in gastric cancer

A novel strategy for combination of clofarabine and pictilisib is synergistic in gastric cancer

  • Transl Oncol. 2022 Jan;15(1):101260. doi: 10.1016/j.tranon.2021.101260.
Shayan Khalafi 1,  Shoumin Zhu 2,  Rimpi Khurana 3,  Ines Lohse 4,  Silvia Giordano 5,  Simona Corso 5,  Hassan Al-Ali 6,  Shaun P Brothers 7,  Claes Wahlestedt 7,  Stephan Schürer 8,  Wael El-Rifai 9
Affiliations

Affiliations

  • 1 Department of Surgery, Miller School of Medicine, University of Miami, Rosenstiel Medical Science Bldg, 1600 NW 10th Ave, Room 4007, Miami, FL 33136-1015, United States.
  • 2 Department of Surgery, Miller School of Medicine, University of Miami, Rosenstiel Medical Science Bldg, 1600 NW 10th Ave, Room 4007, Miami, FL 33136-1015, United States; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, United States.
  • 3 Department of Pharmacology, Miller School of Medicine, University of Miami, Miami, FL 33136, United States.
  • 4 Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Molecular Therapeutics Shared Resource, Sylvester Comprehensive Cancer Center, University of Miami, FL 33136, United States.
  • 5 Department of Oncology, University of Torino, Candiolo 10060, Italy; Candiolo Cancer Institute, FPO-IRCCS, Candiolo 10060, Italy.
  • 6 Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Neurological Surgery, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Medicine, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Peggy and Harold Katz Drug Discovery Center, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; The Miami Project to Cure Paralysis, Miller School of Medicine, University of Miami, Miami, FL 33136, United States.
  • 7 Center for Therapeutic Innovation, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Psychiatry and Behavioral Sciences, Miller School of Medicine, University of Miami, Miami, FL 33136, United States.
  • 8 Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Pharmacology, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Institute for Data Science and Computing, University of Miami, Miami, FL 33136, United States.
  • 9 Department of Surgery, Miller School of Medicine, University of Miami, Rosenstiel Medical Science Bldg, 1600 NW 10th Ave, Room 4007, Miami, FL 33136-1015, United States; Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL 33136, United States; Department of Veterans Affairs, Miami Healthcare System, Miami, FL 33136, United States. Electronic address: [email protected].
PMID: 34735897 DOI: 10.1016/j.tranon.2021.101260
Abstract

Gastric Cancer (GC) is frequently characterized by resistance to standard chemotherapeutic regimens and poor clinical outcomes. We aimed to identify a novel therapeutic approach using drug sensitivity testing (DST) and our computational SynerySeq pipeline. DST of GC cell lines was performed with a library of 215 Federal Drug Administration (FDA) approved compounds and identified clofarabine as a potential therapeutic agent. RNA-sequencing (RNAseq) of clofarabine treated GC cells was analyzed according to our SynergySeq pipeline and identified pictilisib as a potential synergistic agent. Clonogenic survival and Annexin V assays demonstrated increased cell death with clofarabine and pictilisib combination treatment (P<0.01). The combination induced double strand breaks (DSB) as indicated by phosphorylated H2A histone family member X (γH2AX) immunofluorescence and western blot analysis (P<0.01). Pictilisib treatment inhibited the protein kinase B (Akt) cell survival pathway and promoted a pro-apoptotic phenotype as evidenced by quantitative real time polymerase chain reaction (qRT-PCR) analysis of the B-cell lymphoma 2 (BCL2) protein family members (P<0.01). Patient derived xenograft (PDX) data confirmed that the combination is more effective in abrogating tumor growth with prolonged survival than single-agent treatment (P<0.01). The novel combination of clofarabine and pictilisib in GC promotes DNA damage and inhibits key cell survival pathways to induce cell death beyond single-agent treatment.

Keywords

Clofarabine; Combination therapy; Drug synergy; Gastric cancer; Pictilisib.

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