Uncommon Gynecologic Cancers

Marcela del Carmen, John O. Schorge, Robert H. Young, Marcela del Carmen, John O. Schorge, Robert H. Young

• Publisher: Wiley-Blackwell
• Year: 2014
• Print ISBN:
  9781118655351
• eBook ISBN:
  9781118655313
• Edition: 1
• Topic: Medicine
• Subtopic: Gynecology, Obstetrics & Midwifery

Rare gynecological cancers kill all too commonly

Gynecological cancer is a frightening prospect for women. It is terrifying also for physicians who need, but often can't find, guidance on how to investigate and appropriately treat the tumors. Rare cancers provide greater challenges as information can be harder to find and more difficult to verify.

Rare Gynecologic Cancers: Diagnosis and Management brings together all you need to know on these life-threatening diseases. Straightforward summaries of pathophysiologic processes lead to the investigations that will improve your diagnostic accuracy. This provides the basis for you to identify effective treatment strategies for your patients. Written by a world-leading team of Editors and Authors and covering cancers of the

•             Ovaries

•             Uterus

•             Vulva

•             Vagina

•             Cervix

Rare Gynecologic Cancers: Diagnosis and Management will guide you to the best life-saving treatment for your patients.

Part 1
General Principles

Chapter 1
Molecular Targets in Gynecologic Cancers

Whitfield Growdon, Rosemary Foster, and Bo Rueda

Vincent Center for Reproductive Biology, Vincent Department of Obstetrics and Gynecology, Massachusetts General Hospital, Boston, MA, USA

Introduction

The past two decades have brought an exponential increase in our understanding of the molecular drivers of cancer. These insights have led to the concept of personalized cancer care where an individual tumor can be interrogated for specific molecular alterations that may render the cancer susceptible to novel therapeutics that target that particular alteration. The advent of HER2 (ERBB2) targeted therapies for HER2 overexpressing breast cancer and EGFR inhibitors for EGFR (ERBB1) gene-mutated lung cancers are notable successes that support the concept that targeting specific molecular profiles can lead to clinical benefit.

Regarding gynecologic cancers, investigators now understand that the underlying drivers of any individual tumor may exhibit marked diversity even if both tumors have identical histology. Identifying key molecular pathways that drive subsets of tumors within ovarian, endometrial, and cervical cancer is crucial to the development of clinical trials utilizing the next generation of targeted therapeutics. This chapter seeks to explore several molecular pathways and proteins that have been shown to contribute to the pathology of significant subsets of ovarian, endometrial, cervical, and vulvar cancers. While the promise of personalized cancer medicine has yet to be fulfilled in gynecologic cancers, therapies targeting the PI3K, MAPK signaling pathways, as well as HER2 and VEGF receptors and PARP protein have been shown to have the potential to improve the therapeutic options for patients.

Phosphoinositol 3-kinase (PI3K) pathway

Oncogenic alterations in the phosphoinositol 3-kinase (PI3K) pathway (Figure 1.1) are frequent in endometrial and ovarian carcinomas [1–3]. PI3K is the upstream activator of Akt, and ultimately mTOR and it contributes to regulation of cell growth, angiogenesis, migration, and survival [2,4]. While three classes of PI3K enzymes have been described, class IA PI3Ks have been most associated with promoting carcinogenesis [5]. PI3K enzymes are activated by receptor tyrosine kinases and G-protein-coupled receptors and transfer phosphate groups to the inositol ring of phosphatidylinositol 4,5 bi-phosphate (PIP2) to produce the signaling molecule phosphatidylinositol 3,4,5 tri-phosphate (PIP3) [1]. This process is negatively regulated by the phosphatase and tensin homologue (PTEN) [5]. Direct downstream mediators AKT and mTOR become activated via phosphorylation leading to transcription events that promote growth, invasion, metastases, and cell survival.

Figure 1.1 PI3K signaling cascade. Schematic showing the PI3K/AKT/mTOR and MAPK pathways and the current agents in development for targeting this cascade.

There are many underlying mechanisms for PI3K pathway activation in cancer, including receptor tyrosine kinase activation or amplification, mutation, deletion, silencing of negative regulators of the PI3K pathway, and activation or amplification of downstream kinase mediators [4]. Correlative investigations have demonstrated a significant prevalence of gain of function mutations in the PIK3CA gene in breast, colon, pancreatic, brain, ovary, and, recently, high-risk endometrial cancers [2,6–12]. Recent reports have suggested that gene amplification affects approximately 20–40% of ovarian, endometrial, and cervical carcinomas across all subtypes, while gain of function mutations occur more commonly in endometrioid endometrial cancer and in clear-cell and endometrioid ovarian tumors at approximately a 20% rate [13–18]. Additionally, PI3K activation via these mechanisms was associated with chemoresistance and worsened survival, suggesting targeted inhibition could potentiate conventional platinum-based chemotherapy [19–24].

Given the high prevalence of PI3K pathway activation in gynecologic cancer, targeted strategies inhibiting this cascade could hold tremendous potential to benefit patients with ovarian, endometrial, and cervical cancer [11,25]. Multiple phase I and II clinical trials in endometrial and ovarian cancer have tested agents that target the PI3K pathway [26–28]. Reports from phase II trials of rapalogs inhibiting the mammalian target of rapamycin (mTOR), a downstream mediator of the PI3K pathway, have revealed both objective responses as well as clinically significant disease stabilization [27,29,30]. In addition to the rapalogs, several other classes of PI3K pathway inhibitors including direct PI3K inhibitors, PI3K/mTOR dual inhibitors, and AKT inhibitors are in development for treating ovarian and endometrial cancer [5,28,31]. Early reports from clinical trials suggest that responses to single-agent blockade have an approximately 30% prevalence, occur with or without gain of function mutations in PIK3CA, and manifest limited response durability resulting in treatment resistance [26, 32–35]. This observation has resulted in the hypothesis that targeted blockade of one overactive protein in a fundamental pathway, such as PI3K, AKT, or mTOR, may not result in significant clinical response. Understanding resistance mechanisms will be critical in the clinical implementation of targeted therapies.

The identification of a biomarker associated with response will be crucial to the success of targeted therapy in general. For the PI3K pathway, PIK3CA gene amplification and gain-of-function mutation in both the catalytic subunit (PIK3CA) and the regulatory subunit (PIK3R1) have been described in ovarian, endometrial, and cervical cancer. Some preclinical and clinical data have suggested that those tumors harboring a mutation have increased sensitivity to PI3K pathway inhibition [24,32,36]. Of the gynecologic malignancies, endometrial cancer has the highest prevalence of these molecular alterations. These data have clear implications for selecting candidates for clinical trials so that accrual can enrich for those patients most likely to respond; however, responses to PI3K pathway have been observed in patients that harbor no mutation or amplification, suggesting that additional criteria need to be utilized to identify those women most likely to respond [37–40]. These observations have been confirmed in phase I trials of PI3K inhibitors, although the most robust responses were witnessed in those patients that carry a tumor with specific gain-of-function mutations [41–55]. Selection of endometrial cancer patients by loss of PTEN or gain-of-function mutation in PIK3CA for clinical trials of agents targeting PI3K or AKT is ongoing and it has yet to be determined whether or not these signatures confer sensitivity to directed therapy.

Mitogen-activated protein kinase (MAPK) pathway

The mitogen-activated protein kinase (MAPK) signaling pathway is another growth-signaling cascade associated with multiple cancers that is an attractive target for the development of targeted therapeutics [56–58]. The receptor tyrosine kinases (RTK) family is one of the more recognized kinase families. The MAPK kinase kinase (MAPKKK) phosphorylates and activates MAPK kinase (MAPKK) that in turn can phosphorylate and activate MAPK by phosphorylation on the Thr and Tyr resides [59]. Members of the GTPase families, Ras and Rho, relay signals from the rece...

Table of contents

• Cover
• Title Page
• Copyright Page
• List of Contributors
• Preface
• Part 1: General Principles
• Part 2: Rare Ovarian Cancers
• Part 3: Rare Uterine Cancers
• Part 4: Rare Cancers of the Cervix, Vulva and Vagina
• Index
• End User License Agreement