Overexpression of XIAP reduces apoptosis arising from
chemotherapy, radiation, and growth factor deprivation [43,46,61]. XIAP antisense knockdown in
cancer cells under stress and primed for apoptosis (e.g., when challenged by chemotherapeutic
agents), enhances proapoptotic signals and tips the apoptotic rheostat towards death. XIAP is highly
expressed in acute myeloid leukemia (AML), glioblastoma, prostate, pancreatic, gastric, and colorectal tumors [47]. In AML, this
overexpression has been associated with poor clinical outcome.
AEG35156/GEM640 (Aegera Therapeutics Inc.) is a 19-mer ASO targeted to human XIAP mRNA
that incorporates 2 -O-methyl chemistry with a phosphorothioate backbone. In vitro and in vivo preclinical proof-of-concept
studies have demonstrated that inhibition of XIAP protein expression by
AEG35156/GEM640 enhances the antitumor activity of chemotherapy in several xenograft models
[62,63]. A phase I dose-escalation tolerability study of AEG35156 as a single agent is currently
underway in the United Kingdom as a 7-day continuous i.v. infusion in patients with advanced
tumors and phase I trials evaluating shorter infusion schedules in combination with docetaxel or
reinduction chemotherapy for AML are also recruiting patients. In addition to standard safety and
efficacy endpoints, these trials will also measure pharmacodynamic endpoints [64].
ISIS 3521 and ISIS 5132 (Isis Pharmaceuticals) are first-generation phosphorothioate ASOs
directed against the mRNA of Protein kinase C- [PKC ] and RAF1, respectively. Protein kinase
C (PKC) belongs to a class of serine threonine kinases that adjust numerous intracellular responses
arising from G-protein-coupled receptors, receptors with tyrosine kinase activity and nonreceptor
tyrosine kinases [65]. Increased PKC expression has been implicated in both oncogenesis and tumor
progression [66,67]. PKC inhibitors affect growth and survival of tumors, promote apoptosis, and
sensitize tumor cells to chemotherapeutic agents [68,69]. ISIS 3521 (also referred to as LY900003
or Affinitak or Aprinocarsen) potently inhibits PKC expression in a wide range of human tumor
types in an isoform-specific manner [70,71]. Systemic administration of ISIS 3521 to nude mice
bearing subcutaneously implanted human tumors suppresses PKC levels in tumor tissue and
inhibits tumor growth of numerous human tumor cell lines, including glioblastoma, breast, pancreatic and lung carcinoma [72–74].
On the basis of the biological evidence implicating PKCs in
human tumorigenesis, and the preclinical activity of ISIS 3521 clinical trials were initiated for the
treatment of cancer.
In phase I single-agent studies of ISIS 3521 [75,76], responses were noted in two patients with
low-grade non-NHL and three patients with ovarian cancer. Dose-limiting toxicities were thrombocytopenia and fatigue at a dose of
3.0 mg/kg/d, and the recommended phase II dose was 2 mg/kg/d
via continuous i.v. infusion. Toxicity at this dose appeared mild, with one of six patients developing grade 3 thrombocytopenia.
