The Evolving Field of Tyrosine Kinase Inhibitors in the Treatment of Endocrine Tumors
Total Page：16
File Type：pdf, Size：1020Kb
REVIEW The Evolving Field of Tyrosine Kinase Inhibitors in the Treatment of Endocrine Tumors Lei Ye, Libero Santarpia, and Robert F. Gagel Department of Endocrine Neoplasia and Hormonal Disorders, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030 Downloaded from https://academic.oup.com/edrv/article/31/4/578/2195020 by guest on 28 September 2021 Activation of tyrosine kinase receptors (TKRs) and their related pathways has been associated with development of endocrine tumors. Compounds that target and inactivate the kinase function of these receptors, tyrosine kinase inhibitors (TKIs), are now being applied to the treatment of endocrine tumors. Recent clinical trials of TKIs in patients with advanced thyroid cancer, islet cell carcinoma, and carcinoid have shown promising preliminary results. Significant reductions in tumor size have been described in medullary and papillary thyroid carcinoma, although no complete responses have been reported. Case reports have described significant tumor volume reductions of malignant pheochromocytomas and paragangliomas. In addition, these compounds showed an initial tumoricidal or apoptotic response followed by long-term static effects on tumor growth. Despite the promising preliminary results, this class of therapeutic agents has a broad spectrum of adverse effects, mediated by inhibition of kinase activities in normal tissues. These adverse effects will have to be balanced with their benefit in clinical use. New strategies will have to be applied in clinical research to achieve optimal benefits. In this review, we will address the genetic alterations of TKRs, the rationale for utilizing TKIs for endocrine tumors, and current information on tumor and patient responses to specific TKIs. We will also discuss the adverse effects related to TKI treatment and the mechanisms involved. Finally, we will summarize the challenges associated with use of this class of compounds and potential solutions. (Endocrine Reviews 31: 578–599, 2010) I. Introduction I. Introduction II. Rationale of Treating Patients with Endocrine Tumor enetic events that cause development of endocrine with Tyrosine Kinase Inhibitors A. Why are certain endocrine tumors resistant to cyto- G tumors fall into two broad categories. The first are toxic chemotherapy? genetic events causing activation of a cell-signaling mol- B. The role of RET in the development of the neural crest ecule that lead to enhanced cell growth or a failure to C. Blockade of tyrosine kinase receptor phosphorylation undergo normal cell death. Examples include mutation of by tyrosine kinase inhibitors genes encoding tyrosine kinase receptors (TKRs) such as III. Preclinical and Clinical Trials of Tyrosine Kinase Inhib- RET (REarranged during Transfection) (1), platelet-de- itors in Endocrine Tumors rived growth factor receptor (PDGFR) (2), KIT (v-kit Har- A. Thyroid B. Pheochromocytoma or paraganglioma dy-Zuckerman 4 feline sarcoma viral oncogene homolog) C. Islet cell tumor and carcinoid (3), and EGFR (epidermal growth factor receptor) (4) as D. Adrenal cortical carcinoma well as signaling molecules that function downstream of IV. Side Effects a TKR such as RAS (5) or v-raf murine sarcoma viral A. Fatigue B. Cardiac effects Abbreviations: ACC, Adrenal cortical carcinoma; AKT, protein kinase B; ATC, anaplastic C. Dermatological side effects thyroid carcinoma; BRAF, v-raf murine sarcoma viral oncogene homolog B1; CEA, carci- noembryonic antigen; CML, chronic myelogenous leukemia; DTC, differentiated thyroid D. Gastrointestinal side effects carcinoma; EGFR, epidermal growth factor receptor; FGFR, fibroblast growth factor re- E. Thyroid dysfunction caused by tyrosine kinase ceptor; FTC, follicular thyroid carcinoma; GDNF, glial cell-derived neurotrophic factor; inhibitors GFR␣1, GDNF family receptor ␣1; GIST, gastrointestinal stromal tumor; HIF, hypoxia-in- V. Summary of Current Experience and Challenges in the ducing factor; IGF-IR, IGF-I receptor; MEN1, multiple endocrine neoplasia type 1; MET, hepatocyte growth factor receptor; MIBG, [131I]meta-iodobenzylguanidine; MTC, med- Use of Tyrosine Kinase Inhibitors ullary thyroid carcinoma; mTOR, mammalian target of rapamycin; NF, neurofibromatosis; PDGF, platelet-derived growth factor; PDGFR, PDGF receptor; PI3K, phosphoinositide 3-ki- ISSN Print 0021-972X ISSN Online 1945-7197 nase; PTC, papillary thyroid carcinoma; RAF, v-raf murine sarcoma viral oncogene ho- Printed in U.S.A. molog; RECIST, response evaluation criteria in solid tumors; RET, rearranged during trans- Copyright © 2010 by The Endocrine Society fection; SDH, succinate dehydrogenase; TKI, tyrosine kinase inhibitor; TKR, tyrosine kinase doi: 10.1210/er.2009-0031 Received July 13, 2009. Accepted June 4, 2010. receptor; TSC2, tuberous sclerosis 2; VEGF, vascular endothelial growth factor; VEGFR, First Published Online July 6, 2010 VEGF receptor; VHL, von Hippel Lindau. 578 edrv.endojournals.org Endocrine Reviews, August 2010, 31(4):578–599 Endocrine Reviews, August 2010, 31(4):578–599 edrv.endojournals.org 579 oncogene homolog B1 (BRAF) (6). Activation of these taining cell survival during the development of the en- molecules by mutation, rearrangement, or amplifica- docrine system. tion can trigger cell transformation. The second group is represented by tumor suppressor genes. Inactivation B. The role of RET in the development of the neural crest of these genes may occur through mutation, deletion, or The RET proto-oncogene was first identified in 1985 epigenetic changes that cause important regulatory de- based on its ability to transform NIH3T3 cells (1). One of fects and ultimately lead to cellular transformation. Ex- RET’s ligands, glial cell-derived neurotrophic factor amples relevant to endocrine tumors include phospha- (GDNF), is a small soluble and secreted protein that was tase and tensin homolog (7), multiple endocrine identified in 1993 (16) based on its ability to prevent death neoplasia type 1 (MEN1) (8), von Hippel Lindau (VHL) of neurons in primary cultures. In a remarkable series of (9), and others. This review will focus mainly on acti- rodent-targeted deletion experiments, performed between Downloaded from https://academic.oup.com/edrv/article/31/4/578/2195020 by guest on 28 September 2021 vated TKRs as well as the related pathways in endo- 1994 and 1996, it was shown that animals with a ho- crine-related cancer and strategies to reverse this mozygous deletion of either GDNF or RET have quite activation. similar phenotypes (16–19). These and other experiments led to the conclusion that GDNF—and its related cousins artemin, persephin, and neurturin—is a ligand for the RET TKR. In an independent search for the GDNF receptor, a II. Rationale of Treating Patients with Endocrine second protein, now named GDNF family receptor ␣1 Tumor with Tyrosine Kinase Inhibitors (GFR␣1)—a member of a family of proteins including A. Why are certain endocrine tumors resistant to GFR␣1–4—was identified and shown to be a RET core- cytotoxic chemotherapy? ceptor (20). Collectively, these studies demonstrated that A characteristic of endocrine cancer is its general resis- the absence of any component of this receptor system tance to DNA-damaging chemotherapies or radiotherapy (GDNF, RET, or GFR␣1) led to a failure of normal mi- that would normally lead to apoptosis of the cancer cell. gration of neural progenitor cells into the developing gas- This is particularly true for cancers with activating muta- trointestinal tract (21). As this story unfolded, it became tions of a TKR. Medullary thyroid carcinoma (MTC), clear that GDNF, expressed in cells of the developing gas- where 60–75% of tumors have an activating mutation of trointestinal tract, interacts with RET and GFR␣1 ex- RET, provides a clear example. As we will discuss below, pressed in neural progenitor cells, enticing them to migrate one of the major functions of RET in normal neurons is to from the neural crest into the gastrointestinal tract (21). prevent programmed cell death (10). There is experimen- The absence of RET (or any other component of the re- tal evidence demonstrating that several different activat- ceptor system) resulted not only in failure to migrate but ing mutations of RET have distinct effects to prevent also neural crest progenitor apoptosis. A similar process apoptosis. In these experiments, activating mutations of also occurs in the developing kidney where an interaction the tyrosine kinase domain at codons 883 or 918 prevent between GDNF and RET mediates the formation of the doxorubicin-induced apoptosis to a greater extent than a urinary collecting system (18, 19). GDNF entices the RET- mutation of the extracellular domain (codon 634) or wild- and GFR␣1-expressing Wolffian duct cells to invade the type RET (11). In other experiments, inhibition of RET mesonephros. Absence of any component of the receptor phosphorylation by a tyrosine kinase inhibitor (TKI) led to system leads to a developmental failure. A pas de trois greater response to irinotecan, a topoisomerase 1 inhibitor between RET/GFR␣4 and a member of the GDNF family that induces DNA damage (12). BRAF, an important com- of ligands, persephin, mediates the normal migration of ponent of TKR downstream pathway, is mutant in an neural crest calcitonin-producing cells into the developing average of 44% of papillary thyroid carcinoma (PTC), and thyroid gland (22, 23). RETϪ/Ϫ mice have a markedly its mutation was also frequently associated with the ab- diminished number of parafollicular C cells