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IAP
IAP
survivin(5) IAP(13)

IAPs are a family of functionally and structurally related proteins, which serve as endogenous inhibitors of apoptosis. Members of IAP gene family function as endogenous inhibitors of caspases.(4) IAPs are regulators of innate immune signaling downstream of pattern recognition receptors such as TLR4, NOD 1 and NOD2, and the retinoic acid-inducible gene-I receptor.(3) A common feature of all IAPs is the presence of a BIR (Baculovirus IAP Repeat) in one to three copies.
The IAP family consists of 8 members, including survivin, bcl-2, TRAIL, XIAP, c-IAPl, C-IAP2, NAIP, apollon, ML-IAP/livin, and ILP-2.(1, 2) XIAP binds caspase-9, caspase-3 and caspase-7, cIAP1 and cIAP2 also bind caspases.(2) Activity of XIAP is blocked by binding to DIABLO (Smac) and HTRA2 (Omi).(2) Survivin is a unique member of the IAP gene family with a potential dual role in apoptosis inhibition and regulation of mitosis.(5, 6) Survivin is a protein encoded by the BIRC5 gene.(7) Located at the tip of chromosome 17, a single survivin gene is extensively alternatively spliced to generate several protein isoforms.(8) Regulation of survivin seems to be linked to the p53 protein. It also is a direct target gene of the Wnt pathway and is upregulated by -catenin.(7)
Silencing of the mitotic regulator and apoptosis, survivin, is a universal requirement for successful tumor suppression in humans.(10) Survivin gene expression is transcriptionally repressed by wild-type p53 and can be deregulated in cancer by several mechanisms, including gene amplification, hypo-methylation, increased promoter activity, and loss of p53 function.(11) Survivin is overexpressed in most human tumors and fetal tissue, but is completely absent in terminally differentiated cells.(7) Survivin is seen in higher tumor grade, more advanced disease, abbreviated survival, accelerated rates of recurrence, and chemotherapy and radiation resistance.(12)

Drugs/Indications
Trial Drugs/Indications
Generic Code Old Code Brand Company Indication trials
birinapant TL32711 TetraLogic  P2: ovarian, peritoneal, fallopian, MDS, CMML: P1/2: solid, AML trials
gataparsen  LY2181308  ISIS 23722 Eli Lilly P2: leukemia, PC; P1/2: HCC trials
idronoxil D04498 NV 06 Phenoxodiol MEI; Novogen P3: Fallopian, Ovarian, Peritoneal; P2: PC; P1: solid trials
sepantronium YM155     Astellas (OSI) P2: NSCLC, lymphoma, melanoma, PC, NHL; P1: solid trials
terameprocol EM-1421     Erimos Last new trial 2007; P2: brain; P1: leukemia, lymphoma, solid, glioma, cervical, HNN trials
AT406 Debio 1143 Ascenta P1: solid, lymphoma, leukemia, AML trials
EZN-3042 Sigma-Tau P1: leukemia trials
HGS1029 AEG40826 Aegera P1: solid, lymphoma trials
LCL161 Novartis P2: BC, MM, leukemia; P1: pancreatic, solid trials
RG0917 GDC-0917, CUDC-427 Roche P1: lymphoma, solid trials
Failed Drugs/Indications
Generic Code Old Code Brand Company Indication trials
AEG35156 GEM 640 Aegera terminated; P2: leukemia; P1/2: CLL, HCC, pancreatic, BC, NSCLC, AML; P1: solid trials
RG7419  GDC0152   Roche Last new trial started in 2007; P1: solid trials


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References

1. JC. R. Apoptosis-based therapies. Nat Rev Drug Discov. 2002;1:111-21.

2. Inhibitor_of_apoptosis. [cited]; Available from: http://en.wikipedia.org/wiki/Inhibitor_of_apoptosis.

3. Damgaard RB G-HM. Inhibitor of apoptosis (IAP) proteins in regulation of inflammation and innate immunity. Discov Med. 2011;11(58):221-31. PMCID: 21447281.

4. Salvesen GS DC. IAP proteins: blocking the road to death's door. . Nat Rev Mol Cell Biol. 2002;3:401-10.

5. Andersen MH SI, Becker JC, Straten PT. The universal character of the tumor-associated antigen survivin. Clin Cancer Res. 2007;13(20):5991-4. PMCID: 17947459.

6. DC. A. Validating survivin as a cancer therapeutic target. Nat Rev Cancer. 2003:46-54.

7. Domagala-Kulawik J, Osinska I, Hoser G. Mechanisms of immune response regulation in lung cancer. Translational Lung Cancer Research. 2013;3(1):15-22.

8. DC. A. New wirings in the survivin networks. Oncogene. 2008;27(48):6276-84.

9. Ward EM, Thun MJ, Hannan LM, Jemal A. Interpreting cancer trends. Annals of the New York Academy of Sciences. 2006;1076(1):29-53.

10. Guha M AD. Survivin as a global target of intrinsic tumor suppression networks. Cell Cycle. 2009;8(17):2708-10. PMCID: 19717980.

11. Mita AC MM, Nawrocki ST, Giles FJ. Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res. 2008;14(16):5000-5. PMCID: 18698017.

12. Kelly RJ L-CA, Citrin D, Janik JE, Morris JC. Impacting tumor cell-fate by targeting the inhibitor of apoptosis protein survivin. Mol Cancer Res. 2011;10:35. PMCID: 21470426.

13. De Almagro M, Vucic D. The inhibitor of apoptosis (IAP) proteins are critical regulators of signaling pathways and targets for anti-cancer therapy. Exp Oncol. 2012;34(3):200-11.