Page 293 - Withrow and MacEwen's Small Animal Clinical Oncology, 6th Edition

272 PART III Therapeutic Modalities for the Cancer Patient

Evidence of biologic effect in the form of upregulation of HSP70 have been developed that target these pathways, with varying
chaperone expression in peripheral blood mononuclear cells degrees of specificity. In experimental mouse models these have
shown promise in breast, colon, lung, brain tumors, and mela-
(PBMCs) has been observed.
VetBooks.ir inhibitors in canine OSA, pulmonary carcinoma, and MCT cell noma, either as monotherapy or combined with conventional
There is in vitro evidence of antitumor activity of HSP90
488–492
drugs or RT.
lines. 472–476 The HSP90 inhibitor STA-1474 has been evalu- Recent studies suggest that polymorphisms in BRCA1
ated in a phase I clinical trial in dogs with spontaneous cancer. and BRCA2 may predispose certain dog breeds to mammary
Upregulation of HSP70 after drug administration was observed tumors 493 ; however, evidence of a similar functional deficit in
in both tumor cells and PBMCs, and clinical responses were DNA repair to those observed in BRCA-mutant humans, which
observed in dogs with MCT, OSA, melanoma, and thyroid might confer sensitivity to PARP inhibitors, is lacking, as is any
carcinoma. 477 information regarding in vitro or in vivo efficacy of this class of
drug in canine or feline cancer.
Poly ADP-Ribose Polymerase and Poly
ADP-Ribose Glycohydrolase Nuclear Export

Poly ADP-ribose polymerase (PARP) is a “nick-sensor” that sig- The transport of proteins between the nucleus and cytoplasm is a
nals the presence of DNA damage and facilitates DNA repair. 478 tightly regulated process. Export of proteins from the nucleus to
The first PARP enzyme was discovered by Chambon et al and the cytoplasm is governed by a series of proteins called the expor-
is now recognized as a superfamily of 18 members, 479 although tins. Exportin 1 (XPO1, CRM1) is a member of this series that
only PARP-1 and PARP-2 are known to act in DNA damage. 480 is responsible for the nuclear export of a broad variety of target
The PARP family are also involved in the regulation of several proteins, including a large number of known tumor suppressor
transcription factors, such as NFκB in modulating the expres- proteins, including p53, survivin, Rb, p21, and IkB. 494 XPO1 is
sion of chemokines, adhesion molecules, inflammatory cytokines, upregulated in many cancers versus normal tissues, and increased
and mediators. 478 Poly ADP-ribose glycohydrolase (PARG) is the expression can be associated with higher tumor grade and inferior
main enzyme in catabolizing PAR to ADP-ribose. To date, only treatment outcomes. 495–497
one single PARG gene has been detected in mammals, encoding Multiple small molecule inhibitors of XPO1 have been devel-
for three RNAs, which generate three isoforms. 478 oped and evaluated preclinically. Small molecule elective inhibi-
PARP has multiple intracellular functions, including signal- tors of nuclear export (SINE) inactivate XPO1 and have shown
ing DNA damage and recognizing and binding to DNA strand considerable selective antiproliferative and proapoptotic activity
breaks generated by DNA-damaging agents (cytotoxic drugs and in multiple solid and hematopoietic human tumor types, 498–501
ionizing radiation). 481 Activation of PARP is one of the earliest and early-phase human clinical trials have been conducted
DNA damage responses. PARP is also a modulator of DNA base with the SINE selinexor with evidence of objective antitumor
excision repair, which constitutes a major mechanism for genomic activity. 502–504
stability. There is increasing evidence demonstrating that both The SINE KPT-335 has in vitro antiproliferative activity
PARP and PARG repair DNA. 479 When PARP binds to DNA in canine tumor cell lines derived from melanoma, lymphoma,
strand breaks, it activates an enzyme causing shuttling of PARP MCT, and OSA, and nuclear exclusion of target proteins such
and, subsequently, opening of the chromatin. PARG enters the as P21 and p53 after KPT-335 treatment has been demon-
nucleus, moves to the PARP substrate, and DNA strand breaks strated. 505,506 Oral KPT-335 was evaluated in a phase I clinical
are repaired. Because of excessive PARG, PAR decreases and thus trial in tumor-bearing dogs: hepatotoxicity, hyporexia, and weight
chromatin returns to its original structure. loss were dose limiting, and clinical responses were observed in
PARP inhibition has been suggested as an important approach several dogs with lymphoma. 506 KPT-335 is being developed as
in sensitizing cancer cells to conventional cancer therapy, lead- a veterinary cancer therapeutic, but at the time of writing it does
ing to early clinical trials with PARP inhibitors as single agents not have FDA approval.
and in combination. 481–483 PARP inhibitors have been shown to
be lethal in BRCA-deficient cells because of persistence of DNA References
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