Page 292 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

CHAPTER 15 Molecular/Targeted Therapy of Cancer 271

addition, dysregulation of UPP function appears to occur in many Many HSP90 inhibitors appear to demonstrate significant
types of cancer, thus potentially rendering them more sensitive to preferential activity against malignant cells versus normal cells.
The HSP90 derived from most tumor cells has a binding affinity
407,412
inhibition.
VetBooks.ir inhibition in vitro, only the boronic acid derivatives appear suit- for the HSP90 inhibitor 17-allylaminogeldanamycin (17-AAG)
Although a number of chemicals appear capable of proteasome
approximately 100-fold higher than HSP90 derived from nor-
able for clinical use and only two drugs, bortezomib (Velcade, mal cells. 436 This may occur as a result of the overaccumulation
Takeda) and carfilzomib (Kyprolis, Amgen), have received FDA of mutated, misfolded, and overexpressed signaling proteins in
approval, for the treatment of human multiple myeloma and tumor cells leading to increased HSP90 chaperone activity and
mantle cell lymphoma. 413–417 Several additional proteasome a greater proportion of the molecule in the bound, active, and
inhibitors are in clinical development. Meaningful antitumor 17-AAG sensitive state. 436
activity has been observed in patients with other hematopoietic Tumor cells display considerable variation in sensitivities to
neoplasms, 418–420 but less activity has been seen in solid tumors HSP90 inhibition. Although the mechanisms underlying this dif-
to date. 421–424 ferential sensitivity are incompletely characterized, some impor-
Bortezomib and the investigational proteasome inhibitor tant characteristics include reliance on certain kinase cascades,
ONX0912 have demonstrated in vitro and/or in vivo (xeno- expression of apoptotic and cell-cycle regulators, and P-glycopro-
graft) antiproliferative effects in canine melanoma and OSA tein expression. 437
cells, 393,425,426 and drugs targeting valosin-containing protein, Many receptor tyrosine kinases targeted by the geldanamy-
another regulator of cellular proteostasis, have shown in vitro cins may have important roles in canine and feline tumors. For
activity against canine lymphoma cells. 427,428 example, geldanamycins are capable of inhibiting the function
Toxicology studies with bortezomib have been performed in of mutant and wild-type KIT, 438 which is important in canine
dogs, 429 and a biologically effective and tolerable dose has been MCT 439 ; MET, 440 which is expressed in multiple canine tumor
established in golden retrievers with golden retriever muscular types 441,442 ; PDGF receptor, 443 which is expressed in feline
dystrophy. 430 There are no published reports of proteasome inhib- injection-site sarcoma and OSA 444,445 ; and IGF-1 receptor, 438
itor use in veterinary clinical oncology. which is expressed and functional in canine OSA and mela-
noma. 446–448 The geldanamycins are likewise able to attenuate
Heat Shock Protein 90 the function of the Hif-1 protein, a key transcription factor
responsible for sensing and responding to hypoxia and activating
Given the complex nature of cancer and the multiple pathways the angiogenic switch. 433,449,450 They are also able to deplete key
that can be subjugated to contribute to the malignant pheno- antiapoptotic proteins such as mutant p53 and survivin, 451–454
type, an optimal cancer drug might target a variety of onco- contributing to enhanced in vitro sensitivity to standard cyto-
genic pathways simultaneously. One molecular target that has toxic therapies such as RT and chemotherapy when used in
the potential to interrupt a wide variety of pathways important combination. 455–460
in cancer is heat shock protein 90 (HSP90), a molecular chap- Under certain circumstances, HSP90 inhibitors could have
erone responsible for the conformational maturation of many negative effects on cancer outcomes. For example, 17-AAG has
proteins involved in diverse oncogenic activities such as cell been shown to protect colon carcinoma cells from cisplatin-
adhesion/migration/invasion, signal transduction, cell cycle pro- mediated toxicity, 461 whereas it has additive or synergistic activity
gression, angiogenesis, and survival (Table 15.4). HSP90 and when combined with cisplatin against human neuroblastoma and
other chaperones are responsible for ensuring the correct folding OSA cells. 455 In addition, although 17-AAG inhibited primary
and prevention of aggregation of their client proteins. 431 Mis- tumor formation, it potentiated bone-specific mammary carci-
folding and aggregation of proteins lead to ubiquitination and noma metastasis by enhancing osteoclastogenesis in one murine
proteasomal destruction, resulting in proteins with diminished model. 462
function and greatly shortened half-lives. 432 Although several The impressive preclinical data generated with compounds
classes of compound are capable of inhibiting HSP90 chaperone such as HSP90 inhibitors has led to published phase I human
function, 433–435 the best studied are ansamycin antibiotics of the clinical trials of multiple agents, 463–469 including some early com-
geldanamycin class. binatorial studies, 465–467,470,471 although none are yet approved.

TABLE 15.4 Molecules and Processes Targeted by HSP90 Inhibition
Process Targets References
Invasion and migration Urokinase-like plasminogen activator, FAK phosphorylation 507–509
a
Cell cycle progression Cyclin D3, cdk4 510
Signal transduction Akt, Kit, Raf-1, EGFR, HER2, Jun, Lyn, Src, IGF-1R, PDGFR, Met, Bcr-Abl, ILK, 437,438,440,455–458,460,461,510–514
androgen receptor, progesterone receptor, glucocorticoid receptor
Hypoxic response / angiogenesis Hif-1, VEGF, Glut-1, nitric oxide synthase 433,434,437,449,450,456,515
Antiapoptosis Wild-type and mutant p53, survivin 435,451–454,512,516
Cell senescence Telomerase 517,518
a Urokinase-like plasminogen activator activity appears to be inhibited by geldanamycin class drugs through a mechanism other than HSP90 inhibition. EGFR, Epidermal growth factor receptor; HIF-1,
hypoxia-inducible factor-1; IGF-1R, insulin-like growth factor receptor 1; ILK, integrin-linked kinase; PDGFR, platelet-derived growth factor receptor; VEGF, vascular endothelial growth factor.