REVIEW

The Evolving Field of 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 , islet cell , 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 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. 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 -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 (15). sence of radioiodine sensitivity (13). This body of work was advanced by other investigators Therefore, although TKRs are called “growth factor who demonstrated that RET activation by GDNF led to receptors,” in fact and perhaps more importantly, they increased tyrosine phosphorylation of the receptor and also function as survival agents during normal embry- downstream signaling molecules. RET tyrosine 1062 ological development and differentiation. In this sense, phosphorylation activates at least three independent path- RET is one of the best studied receptors and plays a ways: RAS/v-raf murine sarcoma viral oncogene homolog critical role in the normal development of the enteric (RAF)/ERK/MAPK, JNK (c-Jun N-terminal kinase), and nervous system, kidney (14), and parafollicular C cell phosphoinositide 3-kinase (PI3K)/protein kinase B (AKT). (15). In the following discussion, we will use RET as an There has been extensive analysis of the mechanism by example to describe the importance of TKRs in main- which the absence of GDNF (or RET inactivation) leads to 580 Ye et al. Tyrosine Kinase Inhibitors in Endocrine Tumors Endocrine Reviews, August 2010, 31(4):578–599

TABLE 1. The relative IC50 of TKI targets in a cell-free assay system (in nanomoles)

Imatinib Vandetanib Motesanib Axitinib Sorafinib Gefitinib Sunitinib TKI (Ref.) (180) (60, 181) (182) (183) (184) XL184 (185) (186) Code name STI571 ZD6474 AMG 706 AG-013736 BAY 43-9006 NA ZD1839 SU011248 VEGFR1 19,500 1,600 2 1.2 NA NA NA 15 VEGFR2 10,700 40 3 0.25 90 0.035 NA 38 VEGFR3 5,700 NA 6 0.29 NA NA NA 30 FGFR1 31,200 3,600 Ͼ2,800 NA 580 NA NA 675 PDGFR␣ NA NA 84 NA NA NA NA 69 PDGFR␤ 380 1,100 NA NA NA NA NA 55 EGFR Ͼ100,000 500 Ͼ3,000 NA Ͼ10,000 NA 14 NA KIT 410 NA 8 NA 68 NA NA 1–10 RET NA 100 59 NA 5.9 4.5 NA 224 Downloaded from https://academic.oup.com/edrv/article/31/4/578/2195020 by guest on 28 September 2021 CRAF 970 NA NA NA 6 NA NA NA BRAF NA NA NA NA 22 NA NA NA MET Ͼ100,000 NA NA NA NA 1.8 3,200 NA ABL 38 NA NA NA NA NA NA NA

IC50 values were extracted from the indicated publications; there has been no systematic comparison of these TKIs in a single assay. NA, Not available; CRAF, v-raf-1 murine leukemia viral oncogene homolog 1. apoptotic neuronal death, one of which is via a nonmito- of gastrointestinal stromal tumors (GIST) (32) where there chondrial pathway dependent upon activation of caspases are activating mutations of KIT and PDGFR. EGFR in- and FAS (24). The antiapoptotic function of RET, its hibitors, gefitinib and erlotinib, have shown therapeutic coreceptor GFR␣1, and ligands figure prominently in dis- benefits for non-small cell harboring so- cussions of how TKIs that target RET or other TKR phos- matic mutations in EGFR (33). Multiple TKRs can be phorylation can lead to rapid tumor death after initiation activated independently or as a feedback mechanism. of such therapy. Consequently, multikinase inhibitors, such as sorafenib [BRAF, vascular endothelial growth factor receptor C. Blockade of TKR phosphorylation by TKIs (VEGFR) inhibitor], motesanib (VEGFR, PDGFR, and There are three different strategies to block TKR ac- KIT inhibitor), sunitinib (VEGFR, PDGFR, and KIT in- tivities. One is by RNA interference, which is more specific hibitor), and ZD6474 (VEGFR, EGFR, and RET inhibi- but less successful in delivery; the second is a monoclonal tor), have been developed and applied in various cancers. antibody, which usually failed to block the constitutive We will begin our discussion of TKI therapy of endo- activation of the mutant receptors; the third is TKIs, a crine tumors with thyroid cancer (Table 1), where the group of small organic molecules that interfere with the largest body of experience and the most compelling case interaction between the kinase domain and ATP or other can be made for soundness of this approach for endo- mechanisms such as allosteric inhibitors, thereby inhibit- crine tumors. ing phosphorylation of the kinase and downstream sub- Individual patient responses are assessed by radiolog- strates. In this review, we focus on TKIs. In fact, the term ical evidence of tumor shrinkage [response evaluation “kinase inhibitors” is more accurate because most of these criteria in solid tumors (RECIST)] (34) and response of compounds are kinase blockers rather than selective ty- biochemical markers. A RECIST partial response is de- rosine kinase blockers. However, the term “TKIs” has fined as a greater than 30% reduction of tumor diameter; been commonly used in this field, and for the convenience responses between ϩ20 and Ϫ30% are defined as stable of the readers, we will keep TKIs in this review. The power disease. A complete response is the disappearance of of targeting an activated oncogene was first demonstrated measurable tumor and is considered the most desirable in acute lymphoblastic and chronic myelogenous leuke- outcome. However, the development of more sensitive im- mia (CML). The identification of the Philadelphia chro- aging techniques that detect even small abnormalities and mosome (25) and its characterization as an activating an emphasis on the development of targeted therapies that rearrangement of the c-abl oncogene 1 (26) led to the de- are cytostatic rather than cytotoxic has led to a rethinking velopment of imatinib mesylate (27), a TKI that targets of RECIST criteria. A newer assessment system, named the c-abl oncogene 1, PDGFR, and KIT. A remarkable series Choi criteria, defines a good response as a 10% decrease of clinical trials of imatinib in CML showed normalization of in tumor size or a 15% decrease in tumor density on con- most CML hematological abnormalities (28–31). Imatinib trast-enhanced computed tomography scan (35). Al- mesylate has also been used successfully in the treatment though there is evolving evidence that the Choi criteria Endocrine Reviews, August 2010, 31(4):578–599 edrv.endojournals.org 581

roid cancer. derived from the thyroid follicular cell include PTC, follicular thyroid carcinoma (FTC), and anaplastic thy- roid carcinoma (ATC), whereas MTC is derived from the parafollicular calcitonin-producing C cells. PTC and FTC are classified as differentiated thyroid carcinoma (DTC). Most of the patients with DTC can be treated successfully with a combination of surgery, radioactive iodine, and TSH suppression; 20-yr survival rates are Downloaded from https://academic.oup.com/edrv/article/31/4/578/2195020 by guest on 28 September 2021 greater than 90% (37). However, metastasis or recurrent DTC is often unresponsive to radio- active iodine or chemotherapy; the 10-yr sur- vival rate in these cases is less than 15% (38). Surgery is the only curative therapy for MTC, but 60–80% have extrathyroidal metastasis at diagnosis (39). Outcomes in patients with dis- tant metastasis of MTC are poor; 5-yr survival rates are less than 50% and are associated with resistance to cytotoxic chemotherapy (40). The poorest outcomes occur in ATC patients, with a mean survival of less than 6 months (41). Genetic alterations in genes that encode TKRs and their downstream signaling pathways are im- portant in the development and progression of all types of thyroid cancer (Fig. 1). We will discuss MTC, because the first and most successful clin- ical trials in thyroid cancer were performed in MTC patients.

1. MTC FIG. 1. Activation of TKRs and their downstream pathways in MTC (A) and follicular The role of RET TKR has been well estab- cell-derived thyroid cancer (B). TKRs are activated by specific ligands or genetic lished in MTC. Genetic mapping studies in the alterations (missense mutation, rearrangement, amplification, or overexpression) and lead to activation of several pathways (RAS/RAF/ERK or RAS/PI3K/AKT) known to be 1990s led to the identification of RET muta- important in the development and maintenance of cellular transformation. These tions in hereditary MTC (42, 43) and a more pathways mediate effects on cell growth, cell survival, metastasis, and angiogenesis. detailed sequence analysis now indicates that Inhibition by a TKI can block the TKRs and their downstream pathways, leading to approximately 50% of sporadic MTCs harbor antitumor effects. an activating mutation of RET (44, 45). More importantly, the presence of a codon 918 so- correctly predict outcome, nearly all clinical trials cur- matic RET mutation, which affects the tyrosine kinase rently use RECIST criteria. domain of the receptor, predicts a high rate of metastasis and death (39). These mutations occur in two situations. Individuals with a germline codon 918 mutation (MEN2B) III. Preclinical and Clinical Trials of TKIs in have aggressive disease and are uncommonly cured of their Endocrine Tumors thyroid carcinoma, even with surgery in the first year of life A. Thyroid (46, 47). This same mutation also occurs as a somatic mu- Thyroid cancer is the most common endocrine tumor. tation and is similarly associated with aggressive disease. According to the Surveillance Epidemiology and End Re- Data obtained from animal models also support an impor- sults (SEER) program (36), there were 37,000 new cases of tant role of Ret in MTC. Transgenic mice with active mutant thyroid cancer and more than 1,500 related deaths in Ret developed MTC (48, 49), and inhibition of RET by bio- 2008. Two major epithelial cell types are involved in thy- logical approaches demonstrated an anticancer effect (50, 51). 582 Ye et al. Tyrosine Kinase Inhibitors in Endocrine Tumors Endocrine Reviews, August 2010, 31(4):578–599

TABLE 2. Publications of phase II clinical trials of TKIs in advanced thyroid cancer

Imatinib (58, 59); Motesanib (64, 109); PDGFR, KIT, RET, VEGFR1, -2, -3, Axitinib (110); Sorafenib (111, 112); Gefitinib (115); c-Fms, Bcr-ABl TKI (Ref.); targets PDGFR, KIT VEGFR1, -2, -3 BRAF, VEGFR1, -2 EGFR Dosage 600–800 mg/d 600 mg/d 125 mg/d 5–7 mg bid 400 mg bid 250 mg/d No. of patients 15 9 93 91 60 30 56 27 Histology (%) PTC 0 0 61 0 50 60 73 41 FTC 0 0 16 0 7 30 19 22 Hu¨ rthle 0 0 18 0 18 30 19 4 ATC 0 0 1 0 3 7 7 19

MTC 100 100 0 100 18 3 0 15 Downloaded from https://academic.oup.com/edrv/article/31/4/578/2195020 by guest on 28 September 2021 Others 0 0 3 0 3 0 0 0 Response (%) CR 0 0 0 0 0 0 0 0 PR 0 0 14 2 30 23 11 0 SD 27 11 67 81 38 53 62 12 PD 6 44 8 8 7 3 16 15 Median PFS (month) NA 6 9.3 11.2 18.1 18.4 15a 3.7 Patients with decreased NA NA 81 NA NA 95 (n ϭ 19) 78 (n ϭ 14)b 33 serum TG (%) Decreased calcitonin (%) NA 0 NA 83 NA NA NA 0 Discontinuation for adverse 20 11 13 14 13 20 25 7 event (%)

NA, Not available; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; PFS, progression-free survival; TG, . a For PTC patient. b For 14 PTC patients.

In addition to RET, other TKRs have also been asso- of achieving these concentrations in humans without the ciated with MTC development and progression. Overex- development of unacceptable side effects (57). Several pression of EGFR and its ligand was reported in MTCs clinical trials were initiated using imatinib doses of 600– (52). Proliferation of TT cell and NIH3T3 cells, expressing 800 mg/d. The results in the two reported studies with a MEN2A or MEN2B mutation, can be effectively inhibited total of 24 patients with MTC showed no reduction of by an EGFR inhibitor (53). MET (hepatocyte growth fac- tumor size, although several had stable disease (58, 59) tor receptor) (54) and fibroblast growth factor receptor 4 (Table 2). (FGFR4) (55) were also reported to be overexpressed in It was a report describing the effect of a VEGFR-tar- MTCs and MTC cell line. geted TKI, ZD6474 (vandetanib), on RET activation (60) The parallels between the efficacy of imatinib in that led Wells et al. (61) to initiate the first phase II clinical PDGFR or KIT mutation-positive GIST tumors and the trial of a TKI in hereditary MTC. Preliminary reports from presence of RET activation in MTC garnered the attention this trial have demonstrated that 25 (83%) of 30 patients of a number of thyroid cancer investigators, leading to had a reduction in tumor diameter. Based upon RECIST participation of patients with MTC in phase I or phase II criteria, 11 patients (six confirmed and five unconfirmed) trials of TKIs (Table 2). Although relatively few of these had a partial response (30% reduction of tumor diameter), studies are complete, preliminary reports presented at sci- and most had significant reductions of serum calcitonin entific meetings offer an overview of their effects. Despite and (CEA) (62). In a recent the fact that MTC and PTC present with different biolog- Phase I/II trial of vandetanib in pediatric patients with ical and clinical behaviors, most of the phase I and II stud- metastatic MTC, two of six children/adolescents with he- ies have not distinguished between these two histological reditary MTC (codon RET 918 mutation) showed a par- types. Therefore, we will discuss these trials in Section tial response, and all six patients had a reduction of tumor III.A.2 on thyroid follicular cell-derived cancer rather volume (63). A randomized prospective phase III trial of than in this section. vandetanib vs. placebo in MTC has completed enrollment. Imatinib was the first TKI evaluated in MTC and other No data are available for this trial. thyroid cancers. Studies from several laboratories demon- Motesanib, a TKI that targets VEGFR, PDGFR, RET, strated that imatinib inhibited phosphorylation of RET at and KIT (Table 1), was evaluated in both MTC and DTC concentrations between 5 and 20 ␮M (56) (Table 1). What (Table 2). The response to motesanib in MTC patients was was not readily appreciated at that time was the difficulty unimpressive (64); only two of 91 patients had a con- Endocrine Reviews, August 2010, 31(4):578–599 edrv.endojournals.org 583 firmed partial response, although 81% of the patients had (77). These findings have made BRAF an attractive target stable disease. Of particular note, motesanib-induced di- for therapy in advanced thyroid cancer. Other genetic ab- arrhea and weight loss were significant issues in the MTC normalities found with some frequency in PTC or FTC and PTC cohorts that led to a dose reduction in many include NTRK1 (neurotrophic TKR type 1) rearrange- patients. Mean plasma concentrations of motesanib were ments (78–81) and RAS mutations (82–84). RAS muta- significantly lower in MTC patients than in DTC patients tions, exclusively Q61R, have also been associated with treated with the same dose of the agent (64), likely related more aggressive tumor types including FTC and ATC to the worsening of diarrhea and a potential explanation (83–86), although other mutations have also been iden- for the relative lack of efficacy in MTC. tified (77). The observation that sorafenib, originally developed as Several independent studies have implicated the VEGF a RAF inhibitor (65), has activity against RET (66), family and their receptors as relevant factors in the devel- Downloaded from https://academic.oup.com/edrv/article/31/4/578/2195020 by guest on 28 September 2021 VEGFR, and PDGFR stimulated several clinical trials of opment and progression of thyroid cancer. A body of thyroid cancer including MTC. Preliminary data from a work from several investigators has demonstrated expres- phase II trial of sorafenib in 19 patients with metastatic sion of VEGFs and their receptors in thyroid cancer, point- MTC found a 68% objective response (durable partial ing to VEGFR-related angiogenesis as an important factor response plus stable disease) (67). There was a greater than in tumor growth and metastasis. Elevated expression of 25% reduction of serum calcitonin and serum CEA in 68 VEGF and its receptors was found in thyroid cancer cell and 42% of the patients, respectively. In addition, Hong lines, tumor tissues, and serum of thyroid cancer patients et al. (68) reported last year a patient with metastatic MTC and correlated positively with high tumorigenic potential bearing a novel somatic RET mutation, who was treated (87–92). Furthermore, inhibition of the VEGF pathway by with sorafenib and tipifarnib. The patient showed a 46% RECIST response after eight cycles of treatment. Al- either inhibition of synthesis (93) or neutralizing antibody though sorafenib was first described as a RAF inhibitor, it (94) can reduce cell proliferation and tumor formation in has limited cellular activity against the BRAF V600E thyroid carcinoma. There is also evidence that a specific mutation. single nucleotide polymorphism of the VEGFA gene, XL 184 is a TKI with activity predominantly against rs699947, is associated with thyroid cancer development RET, VEGFR2, and MET. In a preliminary report of a and regional lymph node metastasis in men (95). Cross phase I study of 36 patients with MTC, 55% had a partial talk between VEGFR2 and RET signaling pathways has response (69); only one patient had progressive disease. been reported in kidney development, suggesting the pos- All patients with a response had a reduction of calcitonin sibility of a similar interaction in thyroid neoplasia (96). and CEA. Responses were observed in patients with or Finally, the evident role of VEGF in tumor expansion and without RET mutations. This observation suggests either vascular function in other tumor types (97) suggests a sim- that RET may be activated by other mechanisms or that ilar but as yet incompletely described role in thyroid VEGFR2, MET, or another kinase has an important role. cancer. A placebo-controlled double-blind phase III trial is ongo- Another TKR implicated in thyroid cancer is EGFR. ing with a goal of enrolling 315 unresectable, locally ad- Overexpression of both EGFR and its ligands has been vanced, or metastatic MTCs; no data are available. found in all types of thyroid cancer, including PTC, FTC, and ATC (98–100). The activation of this pathway has 2. Thyroid cancer derived from the follicular cell been shown to stimulate cell growth and invasion in PTC Abnormalities of TKRs are also involved in malignan- and FTC (101, 102). Although mutation and amplifica- cies derived from the thyroid follicular cells. A RET rear- rangement is the most common genetic abnormality in tion are important mechanisms for EGFR activation in PTC induced by radiation (70–72). BRAF (a serine thre- other tumor types such as lung cancer, there are conflicting onine kinase and an important component of TKR path- results in thyroid cancer: a low frequency in ATC (103) ways) mutations are found in 29–69% of PTC and in and high frequency in PTC (104). A recent study reported 13–35% of poorly or undifferentiated thyroid carcinoma an important interaction between EGFR and the RET/ (73, 74). The presence of a BRAF (V600E) mutation is an PTC rearrangement, showing that RET and EGFR can independent factor contributing to persistent disease or physically interact with each other (53). This same report death in PTC (13, 75). The aggressive tall-cell variant of also describes a growth inhibitory effect of an EGFR TKI PTC shows an even higher frequency (55–100%) of BRAF in normal thyroid and NIH3T3 cell lines, where consti- mutation (76). In a recent study, BRAF mutations were tutively activated RET/PTC3 was expressed. Because of found to be highly prevalent in ATC (44%) and in meta- the high frequency of RET rearrangement in PTCs (30– static radioactive iodine-refractory thyroid cancers (95%) 35%), this discovery makes EGFR a potentially important 584 Ye et al. Tyrosine Kinase Inhibitors in Endocrine Tumors Endocrine Reviews, August 2010, 31(4):578–599 therapeutic target. However, the data from limited clinical afenib was examined in 41 patients with metastatic PTC trials of EGFR inhibitors have been unimpressive. and 15 other patients with other follicular cell histological Overexpression or amplification of other TKRs has subtypes (FTC, Hu¨ rthle, anaplastic) (Table 2). Six of 41 also been identified in thyroid cancer and has been asso- PTC patients (15%) had a partial response, and 23 had ciated with poor outcomes. For example, MET is highly stable disease for more than 6 months. Serum TG levels expressed in PTC and localizes at the invasive tumor edge declined more than 25% in 14 of 18 patients (78%) who (105); IGF-I receptor (IGF-IR) is frequently phosphory- had measurements. There was no correlation between the lated in FTC (106); FGFR1 and FGFR 4 were found to be presence of a BRAF mutation and response, although the overexpressed and activated in thyroid cancer (107, 108). lack of a reliable control group made this observation less The frequent abnormalities of TKRs found in advanced informative. In 10 paired PTC biopsies (before and after thyroid follicular malignancies led to investigations of treatment), four showed a reduction of phospho-VEGFR, Downloaded from https://academic.oup.com/edrv/article/31/4/578/2195020 by guest on 28 September 2021 multiple TKIs. The phase II trial of motesanib, a TKI that phospho-ERK, and VEGF levels, suggesting that this targets VEGFR, PDGFR, RET, and KIT (Table 1), in a agent has antiangiogenic effects. More selective and po- large cohort was the first published study in DTC (109) tent BRAF (V600E) inhibitors have been recently intro- (Table 2). Of 93 patients with metastasis of DTC, 14% duced into clinical trials, including PLX4720 and a new had a partial response, and 67% had stable disease. The class of pyridoimidazolone-containing molecules (113, median progression-free survival was 40 wk. Eighty-one 114). The finding of substantial responses to these com- percent had a reduction of the serum thyroglobulin pounds in melanoma patients with BRAF mutations sug- concentration. gests that they may be effective in advanced thyroid cancer Axitinib is a multikinase inhibitor that targets predom- with BRAF mutations. A phase II trial of gefitinib (115), inantly VEGFR1, -2, -3, and PDGFR1 (Table 1). In a phase an EGFR TKI, demonstrated no responses in 27 patients II study of axitinib (110), 18 of 60 patients had partial with PTC, FTC/Hu¨ rthle, ATC, and MTC (Table 2). In two responses in each of the following histological types: PTC, earlier phase I studies of PKI 166 and AEE 788, at least five eight of 30; FTC, six of 15; MTC, two of 11; and ATC, one patients with MTC were enrolled, and there was no re- of two (Table 2). Thirty-eight percent had stable disease sponse (our observations). These observations suggest for more than 16 wk. Another interesting observation that EGFR may not be a relevant target. from this study was the examination of serum VEGFR and Three TKIs (AMG-706, axitinib, and sorafenib) have KIT, receptors targeted by this agent. The study showed been studied in ATC; in none has there been a clinical a 32 and 35% decrease of soluble VEGFR2 or VEGFR3 response. Preclinical data showed that combinations of and a 13% decrease of soluble KIT, whereas the ligand, EGFR, VEGFR, or IGF-IR TKIs with DNA damage agents serum VEGF, was raised 2.8-fold. The authors concluded had antineoplastic effects in ATC cell lines and athymic from this analysis that VEGFR2 and VEGFR3 were the mice bearing ATC tumors (116–119). There are ongoing primary targets of the therapy. This part of the study is limited in that it does not address these soluble receptor clinical trials of combined TKI and cytotoxic chemother- responses in terms of histological type, making it difficult apy, which may give more promising response. to parse the significance of the data set. However, the In summary, there is compelling evidence for substan- dataset is important because it implicates VEGFR effects tial activity of several TKIs in the treatment of metastatic in the observed responses. Whether the tumor response DTC and MTC. In PTC, there is evidence of activity of was from the target inhibition of VEGFR activity in tumor motesanib, sorafenib, axitinib, and sunitinib. In MTC, tissue or from a systematic inhibition remains to be vandetanib, sorafenib by itself or in combination with tipi- explored. farnib, XL 184, axitinib, motesanib, and sunitinib have As for sorafenib, the RAF, RET, VEGFR, and PDGFR activity in phase I or II trials. The availability and effec- inhibitor, two large cohorts of phase II trials in advanced tiveness of multiple TKIs make it important and helpful to thyroid cancer were recently published. The first report profile genetic events before starting treatment in patients from Gupta-Abramson et al. (111) examined the effects of with thyroid cancer. Identification of specific mutations or sorafenib in 30 patients with metastatic, iodine-refractory abnormalities could provide valuable information in the thyroid carcinoma of several types including PTC, FTC/ decision of target therapy. At present, no consensus has Hu¨ rthle, ATC, and MTC (Table 2). Twenty-three percent emerged on the relative potency of these compounds or of the patients, with either PTC or FTC/Hu¨ rthle histolog- their relative usefulness in hereditary vs. sporadic tumors. ical subtypes, had partial responses, and 53% had stable In MTC, it seems likely that greater understanding of rel- disease. Serum TG levels fell a mean of 70% across all ative potency and duration of response will be provided by follicular histological types. In a second report (112), sor- ongoing phase III trials. Endocrine Reviews, August 2010, 31(4):578–599 edrv.endojournals.org 585

combined chemotherapy or MIBG in approximately 24–55% of patients us- ing RECIST criteria (123, 124). With- out any treatment, the 5-yr survival rate for metastatic paraganglioma/pheo- chromocytoma is approximately 50% (125). Recent insights into the causative molecular events provide opportunities for targeted therapy. Germline muta- tions of seven genes (NF1, VHL, RET, Downloaded from https://academic.oup.com/edrv/article/31/4/578/2195020 by guest on 28 September 2021 SDHB, SDHC, SDHD, and K1F␤) (126), six of which are inactivating and one activating (RET), have been found in genetic tumor syndromes in which pheochromocytoma is a component. Despite the genetic and clinical hetero- geneity, there is evolving evidence that most of these mutations lead to activa- ␣ FIG. 2. HIF-related genetic events in pheochromocytoma and paraganglioma. HIF1 is a ␣ transcription factor that activates a number of biological processes, especially angiogenesis tion of hypoxia-inducing factor 1 mediated by VEGF, PDGF, and other molecules. Its degradation involves hydroxylation by (HIF1␣), a transcription factor that prolyl hydroxylase (PDH) and the subsequent ubiquitylation by the VHL protein ubiquitin- activates a number of biological pro- ligase complex. In transformed cells, SDH mutations lead to accumulation of succinate and inhibition of PDH activity; VHL mutations lead to a failure to form the VHL ubiquitin-ligase cesses, especially angiogenesis medi- complex, thereby reducing HIF1␣ degradation. In both cases, HIF1␣ is stabilized by inhibition ated by VEGF, PDGF, and other of protein degradation. The stabilized HIF1␣ induces the expression of numerous genes that molecules (Fig. 2). VHL disease pro- support tumor angiogenesis including VEGF and PDGF. Increased VEGF or PDGF expression vides the best example. The VHL pro- by the tumor cell can cause autoactivation of tumor cell VEGFR or PDGFR or activation of the same receptors on the endothelial cells, leading to increased angiogenesis. Sunitinib, a potent tein is involved in the degradation of TKI of VEGFR, PDGFR, and KIT, can disrupt these pathways. HIF1␣ and HIF-2 transcription factors through E3 ubiquitin ligase complex- B. Pheochromocytoma or paraganglioma induced ubiquitination (127). Pheochromocytomas/para- Pheochromocytoma and paragangliomas are tumors gangliomas with SDH mutations have been shown to arising from neural crest-derived paraganglia. They may overexpress HIF1␣ and VEGF and have a high level of be sympathetic (-producing paraganglioma microvascularity (128) and a transcriptional signature of or pheochromocytoma, either intra- or extraadrenal) or hypoxia, angiogenesis, and oxidoreductase imbalance parasympathetic (almost all extraadrenal). Approxi- (129). Angiogenesis inhibition has been shown to have a mately one fourth are caused by germline mutations therapeutic benefit for sporadic renal cell carcinoma associated with one of several syndromes: neurofibroma- tosis (NF1), VHL, MEN1, MEN2 (RET), and hereditary (130), and renal cell carcinoma is an important compo- paraganglioma/pheochromocytoma syndromes [succi- nent of VHL disease. Studies have shown high levels of nate dehydrogenase (SDH) subunit B, SDHB; subunit C, VEGF and its cognate receptor correlate with poorer out- SDHC; and subunit D, SDHD]. Somatic mutations of the comes in malignant pheochromocytoma. Expression of ␣ ␣ causative genes occur in a small portion of sporadic tu- HIF1 , HIF2 , endothelial PAS domain-containing pro- mors. Malignant pheochromocytomas are predominantly tein 1, and their target genes is found in paraganglioma associated with inactivating mutations of SDHB either in and pheochromocytoma with VHL and SDH mutations the context of familial paraganglioma syndrome 4 or ap- (131, 132). Collectively, these findings indicate a potential parently sporadic pheochromocytoma with a somatic therapeutic role for targeting components of the VEGFR SDHB mutation where 80% are malignant; malignancy is and its downstream targets in malignant pheochromo- uncommon in VHL, MEN2, NF1, or other paragangli- cytoma. TKIs are one of the first therapeutic agents of oma syndromes (120, 121). The current therapeutic ap- this category to make it into clinical use. proaches utilize [131I]meta-iodobenzylguanidine (MIBG) Sunitinib is an oral TKI that inhibits phosphorylation or a combination of cyclophosphamide, vincristine, and of PDGFR, KIT, VEGFR2, and VEGFR3 (Table 1). In dacarbazine, with comparable rates of response and tox- several proof of concept reports, six patients with malig- icity (122). There is evidence of response to either nant chromaffin tumors had regression after sunitinib 586 Ye et al. Tyrosine Kinase Inhibitors in Endocrine Tumors Endocrine Reviews, August 2010, 31(4):578–599 treatment (Table 3). In the first, treatment of three patients with metastatic paraganglioma (two with and one without

an SDHB mutation) responded positively to cyclic therapy NA with sunitinib (50 mg/d for 4 wk, followed by 2 wk of no Duration of 40 (ongoing) drug) (133). One had a partial RECIST response (Ͼ30% response (wk) reduction of tumor diameter) followed by resection of the residual tumor; reinitiation of sunitinib postoperatively at a lower dose of 35.5 mg was associated with tumor pro- gression. The second patient was treated with a combina- tion of surgery, radiation, and cytotoxic chemotherapy

(cis-platin and etoposide) and developed progressive dis- Downloaded from https://academic.oup.com/edrv/article/31/4/578/2195020 by guest on 28 September 2021 urinary normetanephrines and 78% ease. After six cycles of sunitinib (as described above), the NA 4 patient showed a complete RECIST response (no radio- logically identifiable tumor) in lung and pelvic lymph nodes. The third patient with pulmonary metastasis had been treated with a somatostatin analog and a focal ad- hesion kinase inhibitor without evidence of response. Sub- sequent treatment with cyclic sunitinib was associated significantly with measurable regression of bilateral pulmonary metas- FDG-PET decreased PR Not reported 40 (ongoing) tasis and a 90% reduction in urinary metanephrines. Im- 18 munohistochemical assessment showed a substantial reduction of VEGFR2 expression in the tumor. In a separate report, a patient with an Arg167Gln VHL mutation developed a metastatic and unresectable pelvic pheochromocytoma (that expressed high levels of VEGF and PDGF␤), a renal cell carcinoma, and a well-differen- tiated pancreatic islet (134). She was treated with sunitinib based on VEGF and PDGF␤ expression in to pelvis dacarbazine, and anthracycline; and etoposide and cisplatin

the malignant pheochromocytoma. There was a 50% Sandostatin, FAK inhibitor PR 90% reduction of RECIST evaluable reduction of tumor size for the renal carcinoma, 38% for the pancreatic islet cell tumor and 21% for the malignant pheochromocytoma, and an 85 and 77% reduction of plasma normetanephrine and se- rum chromogranin A, respectively. There was also a sig- -fluorodeoxyglucose positron emission tomography; PR, partial response. 18 nificant improvement in the performance status. SDHC, SDHD, RET The third report was a patient with metastatic para- FDG-PET, ganglioma and germline C196Y SDHB mutation (135). 18 The patient failed treatment with E7974 (a microtubule inhibitor) before starting with sunitinib. After one cycle of sunitinib therapy (50 mg given daily 2 wk on/1 wk off), chest computed tomography scans showed radiographic improvement in her pulmonary lesions, and the extrapul- monary lesions were stable. However, the patient died after 16 wk of sunitinib treatment with progressive disease. The most recent report described sunitinib-induced (37.5 mg/d) necrosis of a malignant pheochromocytoma 18 and a substantial reduction of -fluorodeoxyglucose Tumor response to sunitinib in four cases of paragangliomas and two pheochromocytomas (yr) Gender Histology Germline mutation Previous systemic treat RECIST response Biochemical response positron emission tomography uptake in several meta- Age static lesions after 7 wk of therapy (136). The authors did not use RECIST criteria to evaluate the response, making (Ref.) 1 (133)2 (133) 55 28 M4 M (134) Metastatic paraganglioma 32 Metastatic paraganglioma5 (135) SDHB I127S6 F (136) SDHB 33 C189F 17 Malignant pheochromocytoma F VHL R167Q M None Cisplatin, etoposide, Metastatic radiation paraganglioma Malignant pheochromocytoma NA SDHB Previous C196Y systemic treat E7974 (a microtubule inhibitor) PR Cyclophosphamide, vincristine, Radiographic improvement PR NA 84% reduction of plasma Not reported 16 24 3 (133) 41 F Metastatic paraganglioma No mutation in SDHB, Case no. it difficult to assess the magnitude of the response. TABLE 3. M, Male; F, female; FAK, focal adhesion kinase; NA, not available; Endocrine Reviews, August 2010, 31(4):578–599 edrv.endojournals.org 587

Collectively, these findings have led investigators to de- cinoid showed partial responses in two patients with islet cell velop phase II trials for VHL-related pheochromocytomas carcinoma and one patient with malignant carcinoid. Stable utilizing sunitinib in addition to radiolabeled MIBG. disease was found in 14 and 30% of the patients, respectively What is most significant about these observations is that (142). Treatment with sorafenib showed a partial response in an understanding of the molecular causation, HIF1␣ ex- four of the patients with islet cell carcinoma or malignant pression, and angiogenesis has led to targeted therapy. carcinoid in a preliminary report of a phase II trial (143). There are other phase II clinical trials of TKIs in progress, C. Islet cell tumor and carcinoid including one for imatinib and vatalanib, a TKI which in- Islet cell and carcinoid neoplasms are generally indo- hibits VEGFR1, -2, and -3. lent, and surgical resection may be curative. For patients with metastatic pancreatic islet cell tumor and carcinoid, Downloaded from https://academic.oup.com/edrv/article/31/4/578/2195020 by guest on 28 September 2021 there is no curative systemic treatment available. Soma- D. Adrenal cortical carcinoma tostatin analogs and/or cytotoxic chemotherapy can Although the incidence of adrenal cortical carcinoma reduce tumor size and ameliorate symptoms related to (ACC) is low (0.5–2 cases per 1 million people per year), it is excessive hormone production, but are generally not cur- aggressive with a 5-yr survival rate of less than 10% in pa- ative. Genetic syndromes that cause islet cell or carcinoid tients with metastatic disease. This malignancy has been neoplasms include MEN1, tuberous sclerosis 2 (TSC2), identified in the context of several genetic syndromes includ- NF, and VHL disease. ing Li-Fraumeni (TP53), Beckwith Wiedemann (11p15.5), The tumor suppressor protein TSC2 is of particular Gardner (APC), Carney complex (PRKAR1A), MEN1 interest because it can form a heterodimer with TSC1 and (MEN1), and McCune-Albright syndrome (GNAS1) (144). inhibit the function of mammalian target of rapamycin The identification of IGF-II abnormalities in Beckwith- (mTOR) (137, 138). TSC2 is described as a gatekeeper for Wiedemann tumors led to additional studies that demon- mTOR activation. Lost function of TSC2 can lead to ac- strated overexpression of IGF-II in many sporadic ACCs tivation of mTOR and its related pathways. TSC2 abnor- (145–147). Studies in animal models suggested a major eti- malities can also cause HIF1␣ accumulation (139), ological role for IGF-II in ACC development (148). Addi- thereby activating hypoxia-response genes, analogous to tionally, transcriptional profiling found that the IGF-II gene that described for pheochromocytoma above. The genetic was the most up-regulated gene in ACC (149–151). Preclin- causes of sporadic islet tumor and carcinoid have not been ical studies showed a remarkable reduction of tumor growth fully elucidated. However, TKRs including VEGFR, IGF-IR, by IGF-IR antagonists, presumably by interfering with an EGFR, and PDGFR have been implicated in their develop- IGF-II effect (152). More interestingly, overexpression of ment and progression (140). There are several clinical trials of TKIs in malignant islet EGFR and mutations of BRAF, EGFR, KRAS, and NRAS cell and carcinoid tumors, either completed or in progress have been detected in a subset of ACC (153), indicating that (Table 4). A phase II trial of sunitinib in 66 patients with islet TKIs targeting the Ras/Raf/MEK/ERK and EGFR pathway cell carcinoma and 41 patients with malignant carcinoid may be of benefit in ACC. Two phase II studies of TKIs in found an overall partial response rate of 16.7 and 2.4%, nonresectable ACC patients are now recruiting patients: respectively, and stable disease in 68 and 83%, respectively sunitinib, and a combination of sorafenib and paclitaxel. A (141). Preliminary data from a phase II trial of gefitinib in 39 phase II study of gefitinib in ACC is now complete. No data patients with islet cell carcinoma and 57 patients with car- are available.

TABLE 4. Publications of phase II clinical trials of TKIs in islet cell and carcinoid

Sunitinib (141); VEGFR1, Sorafenib (143); BRAF, -2, -3, PDGFR␣,-␤ Gefitinib (142); EGFR VEGFR2, PDGFR␤ 25–75 mg/d 250 mg/d 400 mg bid TKI (Ref.); targets Pancreatic neuroendocrine Islet cell Islet cell Dosage cancer Carcinoid cancer Carcinoid cancer Carcinoid No. of patients 66 41 39 57 43 50 Responses (%) CR 0 0 0 0 0 0 PR 16.7 2.4 5.1 1.7 10 10 SD 68 83 14 30 7.3 22 PD 7.6 2.4 NA NA NA NA Median PFS (months) 7.7 10.2 NA NA NA NA

NA, Not available; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease; PFS, progression-free survival. 588 Ye et al. Tyrosine Kinase Inhibitors in Endocrine Tumors Endocrine Reviews, August 2010, 31(4):578–599

IV. Side Effects A. Fatigue Fatigue is the most common toxicity associated with TKIs most commonly target not only mutant TKRs, but the TKIs currently being investigated in endocrine tumors. also the normal receptor. Much of TKI-related toxicity The mechanism of fatigue is unclear. In several clinical results from targeting of the normal receptor in nonma- trials, up to 63–82% of patients reported some element of lignant tissues, thereby disrupting normal physiology. A fatigue (111, 112). It is an occasional cause for discontin- more potent TKI may not only be more effective for tar- uation of therapy. geting the receptor in tumor, but may also have greater toxicity. This problem is compounded by the fact that B. Cardiac effects many TKIs used in cancer therapy are multikinase inhib- Cardiovascular toxicity is a significant issue for several itors that have activity against several TKRs. For example, TKIs currently under investigation for the treatment of some of the most effective TKIs for the treatment of MTC endocrine tumors. The most frequent effects include heart Downloaded from https://academic.oup.com/edrv/article/31/4/578/2195020 by guest on 28 September 2021 or PTC have activity against not only RET, but also two failure, hypertension, and QTc (the QTc interval is the QT or three other kinases such as EGFR, VEGFR, PDGFR, interval corrected for heart rate) prolongation (156) MET, KIT, and others not yet defined. Recent studies that (Table 5). The cardiac toxicity may be underestimated show that multikinase inhibitors, those that target multi- because enrollment in a clinical trial requires adequate ple different kinases, have greater efficacy for cancer treat- cardiac function and excludes patients who might be ment suggest that this issue will become more prominent treated when the agent is used in the general population. in the future (154, 155). The challenge will be to balance Drugs with known or potential cardiotoxicity include their greater efficacy with the potential for a broader array imatinib, sunitinib, sorafenib, and vandetanib with of side effects. Table 5 highlights the most common side PDGFR, KIT, and VEGFR as their common targets. An- effects observed with the current TKIs being applied to imal models with a defect of the PDGFR demonstrate endocrine tumors. In the paragraphs that follow, several impaired cardiac remodeling or angiogenesis, leading to of the toxicities will be highlighted, with no attempt to be cardiocyte death and heart failure (157). Interestingly, comprehensive. drugs targeting the EGFR pathway have less cardiotoxic-

TABLE 5. Percentage of each adverse event seen in more than 20% of the patients for at least one TKI

Imatinib Imatinib Motesanib Motesanib Axitinib Sorafenib Sorafenib Gefitinib TKI (Ref.) (58) (59) (109) (64) (110) (111) (112) (115) Constitution Fatigue 13 46 37 50 63 82 Weight loss 40 20 25 60 82 Musculoskeletal pain 57 Arthritis 20 Hoarseness 20 7 Rhinorrhea/URI 20 Anorexia 27 25 30 20 57 11 Headache 26 22 7 16 Dermatology Rash 27 22 15 80 78 52 Stomatitis/mucositis 25 47 Palmar-plantar erythema 15 93 62 Alopecia 43 73 Gastrointestinal Diarrhea 11 59 37 48 80 75 41 Nausea/vomiting 6 33 28 24 33 30 55 19 Dyspepsia/abdominal bloating 63 Abdominal pain 33 30 20 68 Pulmonary Dyspnea/cough 27 16 Cardiovascular Hypertension 56 25 28 43 43 Psychology Depression/mood change 30 Neurology Paresthesias/neuropathy 20 21 Endocrine Hypothyroidism/increased TSH 60 22 37 33

URI, Upper respiratory infection. Endocrine Reviews, August 2010, 31(4):578–599 edrv.endojournals.org 589 ity, although the first reported TKI-related cardiotoxicity most common manifestation is rash; others include pal- was an ERBB2 inhibitor, targeting a member of the EGFR mar-plantar erythrodysesthesia, stomatitis, alopecia, skin family (157). and hair hyper- or hypopigmentation, and skin cancer. Imatinib-related heart failure results from mitochon- Most of these skin toxicities are dose-related and are seen drial dysfunction, first noted and evaluated in CML pa- at therapeutic doses. Rash typically presents within the tients (158). Sunitinib-related cardiotoxicity has been first 2 wk of TKI treatment; some patients improve despite investigated in GIST patients. Up to 28% of patients continued therapy with the TKI. The incidence of skin rash treated with sunitinib showed left ventricular dysfunction is dose-related and occurs with the highest frequency with and a parallel dose-dependent increase of blood pressure sorafenib [80% have skin rash, and 93% have palmar- (159). Mechanisms include inhibition of AMP-activated plantar erythrodysesthesia at the highest tolerated doses

protein kinase and the ribosomal S6 kinase (160). The (111, 112)] and is seen with lesser but substantial percent- Downloaded from https://academic.oup.com/edrv/article/31/4/578/2195020 by guest on 28 September 2021 ribosomal S6 kinase is essential for providing a high level ages of patients treated with sunitinib, vandetanib, and XL of ATP for the cardiocyte. Other mechanisms are almost 184. A rare but concerning dermatological manifestation certainly involved because sunitinib is one of the most is the development of cutaneous squamous cell carcinoma nonselective TKIs, binding to 57 of 317 kinases tested after treatment with several of the TKIs used in thyroid (161). Sorafenib is known to induce acute coronary syn- cancer trials. Although there are few data from random- dromes, and 43% of the advanced thyroid cancer patients ized clinical trials and the true incidence is unclear, there treated with sorafenib developed therapy-related hyper- is the clear sense that skin cancer occurs more frequently tension (111, 112). CRAF (v-raf-1 murine leukemia viral in TKI-treated patients, particularly those with pretreat- oncogene homolog 1) inhibition is important in this pro- ment sun-induced skin abnormalities. cess (157). Moreover, inhibition of VEGFR signaling by Although there is not complete consensus on the cau- both sunitinib and sorafenib may also contribute to sation of the skin changes seen in TKI-treated patients, the treatment-related cardiotoxicity (162). important role of the EGFR in epidermal growth and in- In the clinical usage of these TKIs, hypertension should nervation (164) suggests that its inhibition may be one of be treated promptly because there is evidence that it is an the key mechanisms. In particular, therapeutic agents that important component in the development of cardiomy- include the EFGR as a target are associated with a higher opathy. Therapy frequently requires multidrug therapy or incidence of dermatological manifestations (165, 166). a dose reduction of the TKI. In a small percentage of pa- Additionally, inhibition of KIT, VEGFR, and PDGFR may tients, it has been necessary to discontinue the TKI because also be involved in TKI-related skin disorders. of severe hypertension. Hypertension has been a signifi- Most dermatological manifestations can be managed cant side effect for most of the TKIs used in thyroid cancer by application of corticosteroids and other local therapies clinical trials. (167). Use of agents that block UV irradiation is essential The multikinase TKIs, particularly those that target for patients on TKI therapy with sun exposure. Severe VEGFR, may cause prolongation of the QTc interval. The manifestations such as hand-foot syndrome (a severe form mechanism appears to be a malfunction of ion channels, of palmar-plantar erythema) may require a TKI dose re- presumably regulated by TKRs, that leads to prolongation duction or discontinuation. A form of vitamin K3 (men- of cardiac muscle repolarization (163). This prolongation adione topical cream), which can activate EGFR, is now has been associated with cardiac conduction abnormali- being evaluated in the treatment or prevention of EGFR ties and may lead to arrhythmias, bradycardia and syn- inhibitor-induced skin toxicity (168). cope, and torsades de pointes, a specific type of ventricular tachycardia. A number of other commonly used drugs, D. Gastrointestinal side effects such as psychotropics, antimicrobials and antihistamines Gastrointestinal side effects are commonly associated and electrolyte and mineral abnormalities may prolong with the group of TKIs used to treat endocrine tumors. the QTc interval and should be avoided in patients re- These side effects include nausea, vomiting, diarrhea, dys- ceiving this class of TKIs (163). In the thyroid cancer pepsia, abdominal pain and bloating, and malabsorption. clinical trials, prolongation of the QTc interval has been Although most TKIs used to treat endocrine tumors cause observed and is an occasional cause for discontinuation diarrhea, there are drug-related differences in the fre- of the TKI. quency of diarrhea. For example, patients with metastatic MTC commonly have diarrhea related to their tumor. C. Dermatological side effects Motesanib treatment of patients with MTC resulted in Dermatological manifestations occur frequently in en- diarrhea and weight loss and necessitated dose-reduction docrine tumor patients treated with TKIs (Table 5). The related to this toxicity. In patients treated with the initial 590 Ye et al. Tyrosine Kinase Inhibitors in Endocrine Tumors Endocrine Reviews, August 2010, 31(4):578–599 dose throughout the study, plasma concentrations of V. Summary of Current Experience and motesanib were lower in MTC than DTC patients and Challenges in the Use of Tyrosine may provide an explanation for the low percentage of Kinase Inhibitors partial responders seen in the MTC cohort (64). The gas- The last 4 yr have seen a remarkable transformation in our trointestinal toxicity associated with TKIs may also be thinking about the management of endocrine cancer. The associated with effects on EGFR-mediated chloride secre- discovery that GIST tumors, caused by activating muta- tion (169). Therapy is supportive and includes antinausea tions of KIT and PDGFR, respond to imatinib (32) raised agents and antidiarrheal agents. the question of whether endocrine cancer associated with activating TKR mutations might respond similarly to TKIs E. Thyroid dysfunction caused by TKIs that target the activated kinase. The answer was rapid and

Thyroid dysfunction, especially hypothyroidism, has decisive; patients with activating mutations of the RET Downloaded from https://academic.oup.com/edrv/article/31/4/578/2195020 by guest on 28 September 2021 been associated with TKI use in patients with intact thy- protooncogene respond, some dramatically. Individual roid glands. Hypothyroidism occurred in 36–46% of case reports in pheochromocytoma have followed. The patients taking sunitinib in prospective studies (162). In- largest experience with this class of agents is in MTC dividual case reports have been documented with other where 10–45% developed partial responses and 30–90% TKIs (163). This class of drugs can impair thyroid function have had stable disease after 1 yr of treatment; the mag- in several ways. The first is direct inhibition of sodium- nitude of RECIST-evaluable response varies from 0–50%, iodide symporters (164); the second is inhibition of thy- and the longest duration of response is approximately 4 yr. roid hormone organification by antiperoxidase activity The response rate in MTC may actually be greater, because (165); the third is the development of a destructive form of the three-dimensional structure of the tumor—created by the thyroiditis (166); and the fourth is by increasing thyroid nearly universal presence of amyloid—may not shrink de- hormone clearance (167). There is no consensus about spite the death of cells between the sheets of amyloid. which of these mechanisms is most important or whether Despite the very promising initial results, a sobering there are others. Hypothyroidism may be difficult to di- reality has confronted investigators in the field. These agnose because of the overlap of signs and symptoms of agents are not likely curative, and maintenance of effect hypothyroidism with those caused by metastatic cancer or may require continuous therapy. Although it is possible other side effects of TKIs (fatigue, dry skin, or hair that a significant number of patients will have prolonged changes) that mimic hypothyroidism. It is important to responses with continued therapy, similar to the effects of evaluate thyroid function, including free T4 and TSH imatinib in CML and some GIST tumors, it is clear that (168) levels, basally and at regular intervals during TKI TKIs as monotherapy will not deliver a knockout blow to treatment. most endocrine cancers. Although none of the TKIs has The use of TKIs to treat thyroid cancer creates a unique received Food and Drug Administration approval for the situation. Patients who have undergone total thyroidec- treatment of endocrine cancer, discussion in the MTC field tomy for thyroid cancer are dependent upon thyroid re- is already focused on what types of therapies should be placement. Suppression of the plasma TSH concentration combined with TKIs to enhance their effects. The experi- is an important component of therapy for patients with ence combining sorafenib with tipifarnib, a farnesylation thyroid cancer; development of hypothyroidism in this transferase inhibitor, suggests that this approach may group may abrogate the beneficial effect of the TKI. Al- have value (68). There are a number of potential combi- though this is not an issue in MTC because there are no natorial targets for use with TKIs. First on the list are other TSH receptors on C cells, hypothyroidism occurs with TKRs that contribute to or partner with RET to promote some frequency in TKI-treated patients. At least one im- transformation. One report describes cross talk and phys- portant mechanism of hypothyroidism in thyroid cancer ical interaction between RET and EGFR (53). There is also patients treated with TKIs is malabsorption of thyroid evidence for a role of VEGFRs. Not only is the VEGFR hormone. This is based on the fact that patients with TKI- expressed in MTC tumors, but agents with demonstrable induced diarrhea not only lose weight but also may de- efficacy (ZD6474, sorafenib, sunitinib, and XL184) also velop magnesium or vitamin D deficiency and, in patients target VEGFR. Other TKRs such as MET (54) and FGFR with hypoparathyroidism, hypocalcemia. This is a partic- (55) are also expressed in MTC, and inhibition of these ular problem in MTC patients because of underlying mal- receptors may contribute to the efficacy of some other absorption and diarrhea caused by the hormonal products TKIs (XL184). Second, there are other signaling pathways of the tumor. Thyroid hormone doses as much as one third that may contribute to the development of MTC. These to one half higher than normal may be required to nor- include genetic changes that regulate p18, p27, PI3K, wnt/ malize the TSH concentration. ␤-catenin pathway, mTOR, and nuclear factor ␬B (170, Endocrine Reviews, August 2010, 31(4):578–599 edrv.endojournals.org 591

171). Agents that target each of these pathways are in 200,000 new cases of lung and 220,000 cases of breast clinical trials for other malignancies, and it seems likely cancer each year compared with 3000–4000 cases of all that studies combining one of these agents with an MTC- metastatic endocrine cancer. For an endocrine oncology active TKI will be developed. Third, several types of so- effort to be successful, it will be necessary to learn from matostatin receptor are expressed by the normal and studies performed in these more common cancer types. transformed C cell (172, 173). Although evidence is scant There are several reasons for optimism. Cancer charac- that treatment of MTC patients with somatostatin analogs terization is very quickly changing from a categorization of any type have demonstrable value (174), it is possible system based on histological features to one based on mo- that a combination of a somatostatin analog with a TKI lecular abnormalities. There is a growing consensus that would have therapeutic value because there are links be- two malignant tumors of very different histological type (e.g., endocrine and lung cancer), each with a mutation of tween somatostatin receptor activation and downstream Downloaded from https://academic.oup.com/edrv/article/31/4/578/2195020 by guest on 28 September 2021 TKR signaling pathways. the same signaling molecule, may respond similarly to a There is a similar thought process evolving in other therapeutic agent that targets the specific activated path- endocrine-related tumors. Preliminary data show efficacy of ways, whereas tumors of the same histological type but sunitinib in pheochromocytoma (133, 134), islet cell carci- with different molecular abnormalities may respond very noma, and carcinoid (141). Combining this therapeutic differently. agent with other promising agents such as an mTOR inhib- The challenge for the endocrine community is to learn itor (RAD001) is being explored in other malignancies (175) as much as possible about the nature of the signaling defect and may be relevant to endocrine tumors (176). for each tumor and extract as much information as pos- The challenge is to select a target that will synergize sible from each clinical trial. This will require greater or- with and enhance the effect of a specific TKI. This is a ganization, development of shared resources to accurately daunting task because there are multiple potential targets assess signaling defects, categorization of the impact of and pathways, and more importantly, there are as yet in- targeted therapies on specific signaling defects, and finally, completely understood feedback loops between many of development of methods to use this information to inform these pathways. For example, treatment of glioblastoma future combinatorial therapy. Because many of these with rapamycin can induce activation of Akt pathway in approaches are now being developed in the oncological com- the cancer cell leading to disease progression that is cor- munity, it will be important to seek partners in this commu- related with Akt activation (177). This phenomenon may nity experienced with these techniques. By combining occur because inhibition of mTOR by rapamycin leads to information derived from many different tumor types, suc- reduction of S6 kinase 1, resulting in release of an inhib- cessful strategies for treatment of endocrine will evolve. itory effect of mTOR and activation of Akt. A new and evolving technology is the simultaneous in- Acknowledgments terrogation of multiple signaling pathways, analyzing for mutation, expression, and phosphorylation of these path- We are grateful to the Kosberg Foundation and to John Ball for generous ways. By identifying all common mutations in a tumor, it research support (to R.F.G.), and to the American Thyroid Association for a Thy-Ca Research Grant (to L.S.). is possible to use sophisticated modeling of signal trans- duction pathways to predict the impact of any particular Address all correspondence and requests for reprints to: Robert F. therapy. Through iterative processes that combine actual Gagel, M.D., Head, Division of Internal Medicine, The University of experimental data with sophisticated modeling, it is pos- Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1463, Houston, Texas 77030. E-mail: [email protected]. sible to predict the impact of a targeted therapy in the Current address for L.Y.: Shanghai Center for Endocrinology and context of a particular constellation of mutant genes (178, Metabolism, 197 Ruijin 2nd Road, Ruijin Hospital, Department of En- 179). 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