Targeting HER2 in ovarian and uterine cancers: Challenges and future directions

Teplinsky, Eleonora; Muggia, Franco M.

doi:10.1016/j.ygyno.2014.09.003

Cited by 54 publications

(33 citation statements)

References 66 publications

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“…An understanding of the significance of HER2 expression in epithelial ovarian cancer is evolving [122]. Rates of objective response in clinical trials of single agent trastuzumab, pertuzumab or lapatinib in patients with advanced, refractory ovarian cancer have been modest, and no significant change in median PFS was observed with the addition of pertuzumab to carboplatin/paclitaxel in a randomized phase II study of patients with relapsed, platinum-sensitive ovarian cancer [123,124,125,126].…”

Section: Implications Of the Molecular Characterization Of Epithelmentioning

confidence: 99%

“…In this context, it is worth noting the relatively low frequency of ERBB2 amplification or mutation observed in high-grade serous ovarian cancer [16] (Table 2). Furthermore, the higher frequencies of amplification in ERBB2 reported in some studies of clear cell and mucinous carcinomas of the ovary suggest that anti-HER2 directed therapy may be more beneficial in these subgroups (Table 1 and Table 2) [22,37,122]. …”

Section: Implications Of the Molecular Characterization Of Epithelmentioning

confidence: 99%

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Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment

Rojas

Hirshfield

Ganesan

et al. 2016

IJMS

203

177

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Epithelial ovarian cancer is a highly heterogeneous disease characterized by multiple histological subtypes. Molecular diversity has been shown to occur within specific histological subtypes of epithelial ovarian cancer, between different tumors of an individual patient, as well as within individual tumors. Recent advances in the molecular characterization of epithelial ovarian cancer tumors have provided the basis for a simplified classification scheme in which these cancers are classified as either type I or type II tumors, and these two categories have implications regarding disease pathogenesis and prognosis. Molecular analyses, primarily based on next-generation sequencing, otherwise known as high-throughput sequencing, are allowing for further refinement of ovarian cancer classification, facilitating the elucidation of the site(s) of precursor lesions of high-grade serous ovarian cancer, and providing insight into the processes of clonal selection and evolution that may be associated with development of chemoresistance. Potential therapeutic targets have been identified from recent molecular profiling studies of these tumors, and the effectiveness and safety of a number of specific targeted therapies have been evaluated or are currently being studied for the treatment of women with this disease.

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Section: Implications Of the Molecular Characterization Of Epithelmentioning

confidence: 99%

Section: Implications Of the Molecular Characterization Of Epithelmentioning

confidence: 99%

Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment

Rojas

Hirshfield

Ganesan

et al. 2016

IJMS

203

177

View full text Add to dashboard Cite

show abstract

“…V klinických zkouškách byly testovány specifické inhibitory EGFR erlotinib, gefitinib a canertinib a terapeutická protilátka cetuximab. Jako inhibitory ERBB2 byly testovány lapatinib a terapeutická protilátka trastuzumab [40][41][42]. V žádné z těchto studií však nebylo dosaženo požadova-ného terapeutického efektu a rovněž nebyla prokázána korelace mezi expresí receptorů a terapeutickým efektem.…”

Section: Geny Regulující Buněčný Cyklus Rb1 Ccne1unclassified

Molecular Mechanisms of Carcinogenesis of Epithelial Ovarian Cancers

Müllerová¹,

Müller²,

Křivánková³

et al. 2016

Klin Onkol

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1 Gynekologicko-porodnické oddělení, Nemocnice Nové Město na Moravě 2 Regionální centrum aplikované molekulární onkologie, Masarykův onkologický ústav, Brno SouhrnVýchodiska: Epiteliální ovariální karcinomy jsou v české populaci jednou z nejčastějších příčin úmrtí na gynekologické malignity. Tato skupina nádorů je charakterizována značnou heterogenitou jak z hlediska její patogeneze, tak i odpovědí na terapii. Je otázkou, zda pokroky v objasnění molekulární patogeneze jednotlivých typů epiteliálních ovariálních karcinomů mohou v budoucnu přispět k aplikaci cílené personalizované léčby. Cíle: Tato práce se snaží shrnout současné poznatky o kancerogenezi a molekulární podstatě epiteliálních nádorů ovaria a uká-zat na možné využití těchto poznatků v klinické praxi. Pro základní charakterizaci epiteliálních ovariálních karcinomů je využit dualistický model, který rozděluje tyto nádory do dvou skupin na základě odlišného původu a mechanizmu kancerogeneze. Typ I zahrnuje low-grade serózní karcinomy, endometrioidní karcinomy, mucinózní karcinomy a Brennerův tumor, typ II pak high-grade serózní karcinomy. Závěr: Nově získané poznatky získané sekvenováním nové generace ukazují zásadní odlišnosti v genetických alteracích u obou skupin nádorů. Rozdíly v genetické nestabilitě mezi oběma skupinami nádorů určují způsob jejich kancerogeneze a poukazují na nové cesty pro aplikaci cílené terapie. Porucha homologní rekombinace a vysoká genetická nestabilita u nádorů typu II je hlavní příčinou jejich senzitivity k platinovým cytostatikům a inhibitorům PARP (poly-ADP ribose polymerase). Na druhou stranu karcinogeneze méně agresivních, ale často rezistentních nádorů typu I je závislá na aktivaci signalizačních drah PI3K/ AKT a RAS/ BRAF/ MEK/ ERK. Cílená inhibice těchto drah u nádorů typu I by tak v budoucnu mohla představovat efektivnější terapii s nižší toxicitou. Klíčová slovanádor ovaria -high-grade serózní ovariální karcinom -low-grade serózní ovariální karcinomendometrioidní karcinom -mucinózní karcinom -nádorová transformace -genetická nestabilita Práce byla podpořena projektem MŠMT -NPU I -LO1413. This work was supported by the project MEYS -NPS I -LO1413.Autoři deklarují, že v souvislosti s předmětem studie nemají žádné komerční zájmy.The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study.Redakční rada potvrzuje, že rukopis práce splnil ICMJE kritéria pro publikace zasílané do bi omedicínských časopisů.The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. MUDr 4S47 ÚvodGynekologické zhoubné nádory před-stavují přibližně 15 % všech nádoro-vých onemocnění ženské populace v ČR. Zhoubné novotvary vaječníků tvoří histopatologicky heterogenní skupinu ná-dorů, z nichž ovariální karcinomy jsou klinicky nejvýznamnější [1]. V současné době existuje celá řada studií zabývají-cích se molekulárními základy ovariální kancerogeneze a výsledky těchto prací významně napomáhají upřesnit klasifikaci ovariálních karcinomů, zlepši...

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“…HER2 is overexpressed in 20% to 30% of common female malignancies, breast and ovarian cancer, and up to 34% of gastroesophageal junction cancers (1,2,4,5). Routine examination of tumor HER2 status and systemic therapy with anti-HER2 antibody trastuzumab have become standard oncology practice for HER2-positive cancers, owing to the significant survival benefits seen (2,5).…”

Section: Introductionmentioning

confidence: 99%

Oncolytic Adenovirus Expressing Monoclonal Antibody Trastuzumab for Treatment of HER2-Positive Cancer

Liikanen

Tähtinen

Guse

et al. 2016

Molecular Cancer Therapeutics

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Monoclonal anti-HER2 antibody trastuzumab has significantly improved the survival of patients with HER2-overexpressing tumors. Nevertheless, systemic antibody therapy is expensive, limited in efficacy due to physical tumor barriers, and carries the risk of severe side effects such as cardiomyopathy. Oncolytic viruses mediate cancer-selective transgene expression, kill infected cancer cells while mounting antitumor immune responses, and have recently demonstrated promising efficacy in combination treatments. Here, we armed an oncolytic adenovirus with fulllength trastuzumab to achieve effective in situ antibody production coupled with progressive oncolytic cancer cell killing. We constructed an infectivity-enhanced serotype 5 oncolytic adenovirus, Ad5/3-D24-tras, coding for human trastuzumab antibody heavy-and light-chain genes, connected by an internal ribosome entry site. Infected cancer cells were able to assemble full-length functional antibody, as confirmed by Western blot, ELISA, and antibody-dependent cell-mediated cytotoxicity assay. Importantly, oncolysis was required for release of the antibody into tumors, providing additional spatial selectivity. Ad5/3-D24-tras showed potent in vitro cytotoxicity and enhanced antitumor efficacy over oncolytic control virus Ad5/3-D24 or commercial trastuzumab in HER2-positive cancer models in vivo (both P < 0.05). Furthermore, Ad5/3-D24-tras resulted in significantly higher tumor-to-systemic antibody concentrations (P < 0.001) over conventional delivery. Immunological analyses revealed dendritic cell activation and natural killer cell accumulation in tumor-draining lymph nodes. Thus, Ad5/3-D24-tras is an attractive anticancer approach combining oncolytic immunotherapy with local trastuzumab production, resulting in improved in vivo efficacy and immune cell activation in HER2-positive cancer. Moreover, the finding that tumor cells can produce functional antibody as directed by oncolytic virus could lead to many valuable antitumor approaches. Mol Cancer Ther; 15(9); 2259-69. Ó2016 AACR.

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Targeting HER2 in ovarian and uterine cancers: Challenges and future directions

Cited by 54 publications

References 66 publications

Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment

Molecular Characterization of Epithelial Ovarian Cancer: Implications for Diagnosis and Treatment

Molecular Mechanisms of Carcinogenesis of Epithelial Ovarian Cancers

Oncolytic Adenovirus Expressing Monoclonal Antibody Trastuzumab for Treatment of HER2-Positive Cancer

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