Carrier 62MC User Manual download pdf (Page 8)

Journal of Oncology 7

Table 4: PARP inhibitors and ovarian cancer.

clinical trial.gov ID Therapeutic regimen Study PI

NCT00753545 AZD2281 in platinum sensitive EOC J. Lederman

NCT00679783 AZD2281 in known BRCA or recurrent EOC

K. Gelman

NCT00749502 MK4827 in BRCA mutant ovarian cancer

NCT00664781 AG014699 in BRCA mutant ovarian cancer R. Plummer

NCT00647062 AZD2281 and carboplatin in BRCA mutant EOC E. Kohn

SMOOTHENED receptor mutations or overexpression of

the Hedgehog ligand leads to uncontrolled cell proliferation.

Bhattacharya et al. [99] studied the role of Hedgehog

signaling in ovarian cancer. They utilized a hedgehog path-

way blocker and studied the proliferation of ovarian tumors.

They noted that PATCHED1 is downregulated in ovarian

cancer and that this low level expression of the PATCHED1

contributed to the proliferation of ovarian cancer cells. Chen

et al. [100] also examined the expression and the functional

role of the hedgehog signal molecules in ovarian cancer.

They reported that the hedgehog molecules (Shh, Dhh,

Ptch, Smo, and Gli 1 proteins) were increased in malignant

disease. Decreased cell proliferation in ovarian carcinoma

cell lines was observed with Hedgehog pathway inhibitor-

cyclopamine.

Recently reported was the eﬀect of IPI-926 (Inﬁnity

Pharmaceuticals, Inc., Cambridge, Mass) a novel inhibitor

of the Hedgehog signaling pathway in ovarian cancer grafts.

Data revealed that treatment with cyclopamine, the natural

product of IPI-926 in animals with primary ovarian cancer

grafts, resulted in tumor growth inhibition. This agent is

currently being explored as a Phase I study in patients with

solid tumors (NCT00761696).

Currently recruiting is a study of GDC-0449 (Genentech,

Inc), a Hedgehog pathway inhibitor, as maintenance therapy

in patients with ovarian cancer in a second or third complete

remission. GDC-0449 will be evaluated in approximately 100

patients with ovarian cancer in second or third complete

remission in a randomized, placebo-controlled, double-

blind, multicenter Phase II trial. Patients are randomized

in a 1 : 1 ratio to receive either GDC-0449 or a placebo

comparator and are stratiﬁed based on whether their cancer

is in a second or third complete remission. The primary

endpoint of the trial is progression-free survival. Secondary

outcome measures include overall survival, measurement of

Hedgehog ligand expression in archival tissue, and number

and attribution of adverse events.

12. MTOR Inhibitors

Numerous investigators have reported alterations in PTEN

in gynecological malignancies [101]. PTEN is a lipid phos-

phatase that is associated with cell cycle G1-phase arrest

and apoptosis through the PI3K/AKT/mTOR pathway [102].

The mTOR pathway is a central regulator of cell growth,

proliferation, and apoptosis. The loss of functional PTEN

either through deletion, mutation, or inactivation leads to

the constitutive activation of PI3K eﬀectors in the absence of

exogenous stimuli. Potential therapies targeting the mTOR

pathway include mTOR inhibitors Temsirolimus (CCI-779),

everolimus (RAD001), and deforolimus (AP23573).

In ovarian cancer, AKT activity is frequently elevated

and is closely associated with the upregulation of mTOR

signaling [103]. High levels of AKT activity in vitro result in

hypersensitivity to mTOR inhibitors [103]. An in vivo study

[104] using xenografts of SKOV-3 cells revealed that RAD001

inhibited tumor growth, angiogenesis, and production of

ascites suggesting the potential of mTOR inhibitors in the

treatment of women with ovarian cancer.

GOG trial 170I has recently closed a Phase II Evaluation

of Temsirolimus (CCI-779, mTOR inhibitor) in the Treat-

ment of Persistent or Recurrent Epithelial Ovarian, Fallopian

Tube or Primary Peritoneal Carcinoma. Currently recruiting

studies include (NCT00926107), a study of the mTOR

inhibitor Temsirolimus (CCI-779) to treat ovarian cancer

with Ca125 relapse only, a Phase I study of DOXIL and Tem-

sirolimus in Resistant Solid Malignancies NCT00703170, and

a Phase I study of Docetaxel and Temsirolimus in resistant

solid malignancies (NCT00703625).

13. Conclusion

Multiple attractive targets for the design of targeted ther-

apeutics in ovarian cancer are currently under investi-

gation. Recent studies employing monoclonal antibodies

have revealed improvements in time to progression. Studies

with tyrosine kinases inhibitors remain in their infancy of

development but have provided the basis for continued

research.

Despite these advances there are multiple goals for

the future. These include a better understanding of the

redundant pathways that exist in cell signaling, creative

targeting of horizontal and vertical signaling pathways,

identiﬁcation of other predictive markers to better identify

a targeted subpopulation of patients that will respond, and

an underlying of the mechanisms of resistance. Achieving

these goals will be of paramount importance in the study of

targeted therapy in ovarian cancer.

References

[1] M. A. Bookman, K. M. Darcy, D. Clarke-Pearson, R. A.

Boothby, and I. R. Horowitz, “Evaluation of monoclonal

humanized anti-HER2 antibody, trastuzumab, in patients

with recurrent or refractory ovarian or primary peritoneal

carcinoma with overexpression of HER2: a phase II trial

of the Gynecologic Oncology Group,” Journal of Clinical

Oncology, vol. 21, no. 2, pp. 283–290, 2003.

1 2 3 4 5 6 7 8 9 10 11 12

Comments to this Manuals

No comments

Carrier 62MC User Manual Page 8

Comments to this Manuals

Related products and manuals for Unknown Carrier 62MC