Investigational therapies up to Phase II which target PDGF receptors: potential anti-cancer therapeutics.

Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by Biblioteka Uniwersytetu Warszawskiego on 02/13/15 For personal use only.

Review

1.

Introduction

2.

Current experience with PDGFR inhibitors

3.

Clinical development of new PDGFR targeted molecules

4.

Conclusion

5.

Expert opinion

Investigational therapies up to Phase II which target PDGF receptors: potential anti-cancer therapeutics Jennifer Arrondeau, Olivier Huillard, Camille Tlemsani, Anatole Cessot, Pascaline Boudou-Rouquette, Benoit Blanchet, Audrey Thomas-Schoemann, Michel Vidal, Jean-Marie Tigaud, Jean-Philippe Durand, Jerome Alexandre & Francois Goldwasser† †

Paris Descartes University, Cochin Hospital, AP-HP, Medical Oncology Department, Angiogenesis Inhibitors Multidisciplinary Study Group (CERIA), Paris, France

Introduction: The platelet-derived growth factor receptor (PDGFR) pathway has important functions in cell growth and, by overexpression or mutation, could also be a driver for tumor development. Moreover, PDGFR is expressed in a tumoral microenvironment and could promote tumorigenesis. With these biological considerations, the PDGFR pathway could be an interesting target for therapeutics. Currently, there are many molecules under development that target the PDGFR pathway in different types of cancer. Areas covered: In this review, the authors report the different molecules under development, as well as those approved albeit briefly, which inhibit the PDGFR pathway. Furthermore, the authors summarize their specificities, their toxicities, and their development. Expert opinion: Currently, most PDGFR kinase inhibitors are multikinase inhibitors and therefore do not simply target the PDGFR pathway. The development of more specific PDGFR inhibitors could improve drug efficacy. Moreover, selecting tumors harboring mutations or amplifications of PDGFR could improve outcomes associated with the use of these molecules. The authors believe that new technologies, such as kinome arrays or pharmacologic assays, could be of benefit to understanding resistance mechanisms and develop more selective PDGFR inhibitors. Keywords: anti-cancer therapies, platelet-derived growth factor, platelet-derived growth factor receptor pathway, targeted therapies Expert Opin. Investig. Drugs [Early Online]

1.

Introduction

The deregulated protein tyrosine kinase activity is of major importance in the pathogenesis of human cancers. Targeted therapy has transformed the approach of the management of various cancers and represents a therapeutic breakthrough. Among tyrosine kinases, the platelet-derived growth factor (PDGF) and its receptors (platelet-derived growth factor receptor [PDGFR]) play critical roles in the regulation of cancer cell processes and are increasingly the target of investigational therapies. This review focuses on the development of PDGFR inhibitors with emphasis on future directions that may help such development. The PDGFR pathway The PDGF family has different ligands, consisting of one of four polypeptide chains: PDGF-A, PDGF-B, PDGF-C and PDGF-D [1]. Each chain is encoded by 1.1

10.1517/13543784.2015.1005736 © 2015 Informa UK, Ltd. ISSN 1354-3784, e-ISSN 1744-7658 All rights reserved: reproduction in whole or in part not permitted

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Article highlights. .

.


.

The platelet-derived growth factor receptor pathway could be a driver for tumor development, by overexpression or mutation or by expression in tumoral microenvironment. Currently, most of PDGFR kinase inhibitors under development are multikinase inhibitors. Selecting tumors harboring mutations or amplifications of PDGFR could improve outcomes associated with the use of these molecules.

This box summarizes key points contained in the article.

an individual gene located on chromosomes 7, 22, 4, and 11 respectively [2]. These polypeptide chains form homo- or heterodimers: PDGF-AA, PDGF-AB, PDGF-BB, PDGFCC, and PDGF-DD. These PDGF isoforms exert their cellular effects by binding to PDGF-a and PDGF-b protein kinase receptors (PDGFRa and PDGFRb). Dimerization of receptors occurs after ligand binding, which can be homo- or heterodimerization (PDGFR-aa, PDGFR-ab, or PDGFR-bb). The PDGF polypeptide chains binds to the receptors with different affinities; PDGF-AA, -BB, -AB and --CC induce aa homodimer receptor, PDGF-BB and --DD induce bb homodimer receptor, and PDGF-AB, -BB, -CC and --DD induce ab homodimer receptor [3]. The interaction of the ligand and its receptor leads to the autophosphorylation of the tyrosine kinase domain activating the intracellular PDGF pathway (Figure 1). When phosphorylated, the tyrosine kinase domain recruits the SH-2 domain containing signal transduction proteins and activates signaling molecules with intrinsic enzymatic activities, such as tyrosine kinase of the Src family, phosphatitdylinositol 3¢-kinase, phospholipase C g 1 and the GTPase activating protein for RAS. The activation of these signaling pathways leads to cell proliferation, survival and cell migration. Therefore, PDGF signaling is involved in many processes in embryonic development and studies in mice with PDGF isoforms or knocked-out receptors have elucidated important roles for this pathway. Evidence for targeting the PDGF pathway for the treatment of cancer and preclinical data

1.2

Overactivity of PDGF signaling can result from mutations or overexpression of PDGF or PDGFR and can lead to tumorigenesis in three manners: autocrine signaling, tumor angiogenesis and elevation of interstitial fluid pressure in tumors (Figure 2). In vitro, selective inhibition of PDGF can inhibit angiogenesis in a sponge angiogenesis model [4]. In vivo, it has been shown that PDGF can stimulate angiogenesis [5] and promote the recruitment of tumor pericytes in knockout mice models [6]. Moreover PDGF has a role in the control of tissue interstitial fluid, and activation of the PDGFR leads to the elevation of interstitial fluid pressure in tumors. 2

The consequence of this elevation is mainly pharmacological and could decrease drug delivery to tumors. Importantly, it has been described that during epithelial-mesenchymal transition, tumor expression of PDGFR increases, leading to the conclusion that epithelial tumors that initially did not respond to PDGF stimulation may be reversible and become responsive to PDGF stimulation [7]. PDGFR activation is documented across many tumor types and may result from mutation, gene fusion, or overexpression. This has mainly been described in the following tumor types: gastrointestinal stromal tumors (GIST) [8], gliomas [9], dermatofibrosarcoma protuberance (DFSP) [10], others types of sarcomas (soft tissue sarcoma, osteosarcoma, synovial sarcoma, Ewing’s sarcoma), hematological diseases [11], prostate cancer [12], liver cancer [13], non-small cell lung cancer [14], breast cancer [15], ovarian cancer [16], and colorectal cancer [17]. Furthermore, stroma cells of solid tumors, including cancer-associated fibroblasts (CAFs), could contribute to tumorigenesis [18]. PDGFR are expressed on CAFs and several reports have described that PDGF stimulation could affect CAF functions. Among these reports, one has shown that tumor-cell derived PDGF recruited CAFs in xenograft studies of breast [19] and lung carcinomas [20]. It has also been reported that transgenic PDGF expression in mouse liver cells resulted in tumor fibrosis and promoted development of hepatocellular carcinoma [21]. Moreover, in mouse models, expression of PDGF promoted recruitment of CAFs and growth of malignant melanoma [22] and liver metastasis of colorectal cancer [23]. All these observations have led to the development of different inhibitors of PDGF signaling and preclinical studies have been performed across different cancer types. Most of these agents, particularly molecules currently approved, are multikinases inhibitors without selective targeting of PDGFR. In glioblastoma cell lines or xenograft models, PDGFR tyrosine kinase inhibitors induced reduction of tumor growth [24]. In prostate cancer, human prostate cancer cells (PC-3) in nude mice showed expression of activated PDGFR and PDGF; treatment with imatinib has led to lower tumor incidence, to smaller tumors and to fewer lymph node metastases compared with control mice [25]. In a mouse model of human ovarian cancer, SU6668, a multikinase inhibitor including PDGFR, exhibited anti-tumor effects, with reduction in tumor growth, ascites production, and metastatic spread [26]; improvement in overall survival (OS) has been demonstrated with SU6668 in mouse models of peritoneally disseminated ovarian cancer [27]. In DFSP tumors, imatinib treatment in cell cultures derived from human DFSP tumors has shown growth reduction [28]. Recently, a more potent selective inhibitor of PDGFR, CP-673451, was effective in vitro to suppress cell viability, to induce cell apoptosis, and to inhibit cell migration in non-small cell lung carcinoma cells and invasion at suppressing non-small cell lung carcinoma tumor growth in vivo [29].

Expert Opin. Investig. Drugs (2015) 24(5)


Investigational therapies up to Phase II which target PDGF receptors: potential anti-cancer therapeutics

PDGF-AA

PDGF-AB

PDGF-CC

PDGF-BB

PDGF-AB

PDGF-CC

PDGF-BB

PDGF-BB

PDGF-DD

PDGF-DD

α

α

Src

α

PI3K

β

β

PL-Cγ

β

RAS

- Cell proliferation - Survival - Migration

Figure 1. PDGF pathway with PDGF receptors and its ligands. PDGF: Platelet-derived growth factor; PI3K: Phosphatitdylinositol 3¢-kinase; PL-Cg: Phospholipase C g.

2.

Current experience with PDGFR inhibitors

Currently approved PDGFR inhibitors are multikinase inhibitors also targeting mostly VEGFR or KIT (Figure 2). These therapies are used in different cancer types and can be under development for others. Imatinib is currently approved for the treatment of GIST (in the adjuvant and metastatic settings) and DFSP. It targets VEGFR, PDGFR and KIT. It was first developed for the treatment of chronic myelogenous leukemia (CML) where its efficacy is due to BCR-ABL targeting. It was then developed in GIST for its ability to inhibit cKIT and PDGFR-a as 5% of GISTs have PDGFR-a mutations, which are exclusive with KIT mutations. Different mutations of PDGFR-a have been described, displaying more or less responsiveness to imatinib. A pooled analysis of 289 PDGFR-a mutant GIST patients suggested that more than one-third of these patients may respond to imatinib [30]. Dose limiting toxicities consisted in vomiting, nausea, edema, or dyspnea. Interestingly, imatinib has been under development in prostate cancer and a Phase II trial evaluated the association of imatinib and docetaxel for castration-resistant prostate cancer with bone metastases. The trial was stopped because of excessive toxicity. In this study, phosphorylated PDGFR (p-PDGFR) was measured in peripheral blood leukocytes. Surprisingly, the expected increased probability of p-PDGFR decline in the imatinib group was associated with lower probability of PSA decline,

shorter progression-free survival and OS. In the control arm treated with docetaxel alone, p-PDGFR expression increased, which correlated with improvement of progression-free survival and OS [31]. These observations led to the hypothesis that imatinib-induced p-PDGFR inhibition could antagonize docetaxel efficacy. In ovarian cancer, several Phase II trials have been performed, but most have shown no or minimal efficacy [32]. Imatinib is currently under development in Phase II trials in non-small cell lung carcinoma, mesothelioma, renal cell carcinoma, and head and neck cancer. Other tyrosine kinase inhibitors targeting PDGFR are approved in different cancer types such as axitinib approved in advanced renal cell carcinoma, pazopanib approved in renal cell carcinoma and in soft tissue sarcoma, regorafenib approved in metastatic colorectal cancer and GIST, sorafenib approved in renal cell carcinoma, hepatocellular carcinoma and differentiated thyroid neoplasm, and sunitinib approved in GIST, renal cell carcinoma and pancreatic neuroendocrine tumors. Because the tyrosine kinases targeted by these therapies are very similar, the toxicity profiles are also similar with mainly hypertension, diarrhea, fatigue, nausea, or hand--foot syndrome. As described above, currently approved therapies targeting PDGFR are not selectively targeted on PDGFR, and except for PDGFR mutated GIST and DFSP, the efficacy that has been demonstrated in clinical trials may mostly rely on the inhibition of other tyrosine kinases as VEGFR.


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Olaratumab Tovetumab


Activating mutation amplification translocation

α

α

β

Axitinib Crenolanib Dastinib Dovitinib Lenvatinib Masatinib Motesanib

Imatinib

Nilotinib Nitedanib Pazopabib Ponatinib Sorafenib Sunitinib Tivozanib

β

Linifanib Orantinib Regorafenib Telatinib Vatalanib

Src

PI3K

PL-Cγ

RAS

STAT

AKT

PKC

RAF MEK

mTOR

ERK

Figure 2. Abnormal PDGF receptors and mechanism of action of PDGFR inhibitors. PDGF: Platelet-derived growth factor; PDGFR: PDGF receptor; PI3K: Phosphatitdylinositol 3¢-kinase; PKC: Protein Kinase C; PL-Cg: Phospholipase C g.

Clinical development of new PDGFR targeted molecules 3.

All trials evaluating PDGFR inhibitor were found on the ClinicalTrials website (ClinicalTrials.gov). Several tyrosine kinase inhibitors and two monoclonal antibodies are under development as shown in Table 1 and their mechanism of action is described in Figure 2. For each molecule, molecular targets and IC50 measure are presented in Table 2 [33-50]. Finally, as shown in Table 3, few molecules are currently studied in Phase II trials for their specific targeting of the PDGFR pathway. The main adverse events reported in the articles of these molecules under development are summarized in Table 4. Phase I and II trials of tyrosine kinase inhibitors which target PDGFR

3.1

Dasatinib is currently approved in hematologic disease (CML and acute lymphocytic leukemia) and is evaluated for the 4

treatment of different solid tumor types. Used as monotherapy, Phase II trials have shown limited activity of dasatinib in several tumor types [51,52] [53-57] and toxicity appears to be important. Current development is mainly focused on combination with chemotherapy or targeted agents in Phase I and II trials. A Phase III trial has evaluated dasatinib in combination with docetaxel in chemotherapy-naive metastatic castration-resistant prostate cancer patients, but showed no survival benefit [58]. Nilotinib is approved for the treatment of chronic myelogenous leukemia. A preclinical study has tested nilotinib in ovarian cancer cells and showed significant inhibition of cell growth in PDGFR-a-positive ovarian cancer cell lines [59]. It has been developed in GIST with Phase II and III trials, with no clinical efficacy demonstrated [60]. Phase II trials are ongoing in melanoma and glioma but only with PDGFR amplification. Nilotinib is generally well tolerated. No combination trials in solid tumors are currently ongoing. Ponatinib is approved for the treatment of CML and acute lymphocytic leukemia. Several Phase II studies are ongoing in different cancer types and especially in GIST with PDGFR



Table 1. PDGFR inhibitors currently under development. Molecule

Phase I trials

Crenolanib


Dasatinib

NSCLC Pancreas GIST

Dovitinib

Lenvatinib

Linifanib

NSCLC Melanoma

NSCLC

Masitinib

Motesanib

Gallbladder Breast

Nilotinib

Nindetanib

NSCLC HCC Glioblastoma

Phase II trials GliomasO GISTO NSCLCO NSCLCR PancreasR,O ProstateR,O OvarianR,O BreastR,O Head and neckR GlioblastomaR MelanomaO EndometrialO GISTR BreastO EndometrialO BladderO ProstateO Salivary glandsO Adrenocortical carcinomaO CRCO StomachO HCCO Biliary tractO NSCLCO MesotheliomaO GlioblastomaO OvarianO MelanomaO HCCO RCCO NSCLCO GliomaO EndometrialO CRCR NSCLCR,O HCCR BreastO PancreasR OvarianR GISTR ThyroidR MelanomaO GlioblastomaO Giant cell tumorO ProstateR GliomasR,O BreastR,O OvarianR,O CRCR,O ThyroidO CervixO Lung (S/NSCLC) O

Table 1. PDGFR inhibitors currently under development (continued). Phase III trials

Molecule

Phase I trials

Ponatinib Prostate

Olaratumab

Orantinib Telatinib Tivozanib

HCCO O

Breast

Tovetumab Vatalanib

ThyroidR HCCO

Phase III trials

MesotheliomaO EsophagogastricO NSCLCO GISTO ThyroidO GISTR GlioblastomaR NSCLCO OvarianO Soft tissueO SarcomaO ProstateO

R

RCCR

Phase II trials

Glioblastoma NSCLC Breast Prostate

Stomach HCCR NSCLCR OvarianR GlioblastomaR Soft tissue carcinomaR ProstateR GlioblastomaR NSCLCR MelanomaR NSCLCR,O MesotheliomaR GISTR PancreasR NeuroendocrineR,O BreastO

RCCR,O

CRCR

CRC: Colorectal carcinoma; GIST: Gastrointestinal stromal tumour; HCC: Hepatocellular carcinoma; O: Ongoing; PDGFR: Platelet-derived growth factor receptor; R: Results available; RCC: Renal cell carcinoma.

HCCO

GISTR,O PancreasO MelanomaO NSCLCR GISTR NSCLCR

CRC: Colorectal carcinoma; GIST: Gastrointestinal stromal tumour; HCC: Hepatocellular carcinoma; O: Ongoing; PDGFR: Platelet-derived growth factor receptor; R: Results available; RCC: Renal cell carcinoma.

mutations. A Phase II trial in non-small cell lung carcinoma and head and neck cancer was discontinued because of blood clot risks. Crenolanib (CP-868,596), in preclinical data, has revealed to be a potent, selective inhibitor of PDGFRb tyrosine kinase, and its 50% inhibitory concentrations is about 1 and 0.4 ng/ ml for a and b receptor types, respectively. It is greater than 100-fold more selective for PDGFR than for other kinases [61]. Crenolanib has been tested in a panel of PDGFRa-mutant kinases expressed in different cell line models, including primary GIST cells, and was significantly more potent than imatinib in inhibiting the kinase activity of imatinib-resistant PDGFRa kinases [34]. Moreover, preclinical data suggest that crenolanib is active against FLT-3 mutation in acute myeloid leukemia [62]. Currently, crenolanib is under development in Phase II trials, especially in GIST with PDGFR deletion. In Phase I trials, dovotinib has been shown to induce adverse events of all grades such as nausea, diarrhea, vomiting, decreased appetite, fatigue, hypertension and hypertriglyceridemia [63]. A Phase II study has also evaluated dovitinib as a


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Table 2. IC50 (nM) of PDGFR inhibitors on PDGFRa and PDGFRb.(continued).

Axitinib [33]

Crenolanib [34] Expert Opin. Investig. Drugs Downloaded from informahealthcare.com by Biblioteka Uniwersytetu Warszawskiego on 02/13/15 For personal use only.

Dasatinib [35]

Dovitinib [36]

Imatinib [37]

Lenvatinib [38]

Linifanib [39]

Masitinib [40]

Motesanib [41]

Nilotinib [42]

Nintedanib [43]

Orantinib [44]

Pazopanib [45]

Ponatinib [46]

Regorafenib [47]

Targets

PDGFRa

PDGFRb

Targets

VEGFR PDGFR KIT PDGFR FLT3 BCR-ABL KIT PDGFR SRC EPH A2 FGFR EGFR PDGFR VEGFR PDGFR KIT VEGFR FGFR KIT RET PDGFR PDGFR VEGFR CSF1R FLT3 KIT KIT PDGFR Lyn FGFR VEGFR PDGFR KIT RET BCR-ABL KIT PDGFR VEGFR PDGFR FGFR PDGFR FGFR VEGFR KIT VEGFR PDGFR KIT RAF BCR-ABL RET FGFR KIT PDGFR VEGFR FLT3 TIE2 VEGFR PDGFR

5

1.6

2.1

3.2

KIT RAF FGFR RET VEGFR PDGFR KIT RAF RET FLT3 VEGFR PDGFR KIT RET FLT3 CSF1R VEGFR KIT PDGFR VEGFR PDGFR KIT VEGFR PDGFR

PDGFR: Platelet-derived growth factor receptor.

6

Table 2. IC50 (nM) of PDGFR inhibitors on PDGFRa and PDGFRb.(continued).

Sorafenib [45]

3

210

27

100

-

51

39

Sunitinib [45]

Telatinib [48]

Tivozanib [49] -

66

540

800

Vatalanib [50]

PDGFRa

PDGFRb

933

1129

75

143

-

15

40

49

-

580


84

71

59

65

-

8

73

215

1.1

7.7

-

22

third-line treatment for GIST and showed modest antitumor activity [64]; others Phase II trials are ongoing with dovitinib alone or in combination with other treatments. Dovitinib has been evaluated in a Phase III trial as a third-line treatment for metastatic renal cell carcinoma and did not show more activity than sorafenib [65]. Lenvatinib has been shown to block migration and invasion of tumor cells with concentrations that inhibit FGFR and PDGFR pathways. Furthermore, lenvatinib could not inhibit cell migration in PDGFR negative cell lines [66]. Phase I and II studies are ongoing with lenvatinib alone or in combination, in different types of tumors without identified PDGFR mutation or overexpression. Recently, a Phase III study has reported an improvement of progression-free survival (PFS) in iodine refractory advanced differentiated thyroid cancer but with major toxicity [67]. It is also currently evaluated in a Phase III trial for first-line treatment of hepatocellular carcinoma versus sorafenib. Linifanib has shown inhibition of PDGFR and c-kit pathways in Ewing sarcoma cells [68]. In Phase II trials, linifanib did not show any improvement of outcome in association with chemotherapy or bevacizumab in colorectal cancer [69], but in lung and hepatocellular carcinoma it has shown activity in monotherapy [70,71]. Others Phase I and II trials are evaluating the efficacy of linifanib, alone or in combination, and a Phase III trial is ongoing in hepatocellular carcinoma comparing its efficacy versus sorafenib.



Table 3. Trials with specific PDGFR targeting. Drug

Phase

Status

Indication

Crenolanib Imatinib Nilotinib Olaratumab Ponatinib

II II II II II

Ongoing Suspended Ongoing Ongoing Ongoing

GIST with D842 mutation or PDGFR deletion Glioblastoma expressing PDGFR Melanoma or gliobastoma with PDGFR amplification GIST or glioblastoma with or without PDGFR mutation GIST with KIT or PDGFR mutation


GIST: Gastrointestinal stromal tumour; PDGFR: Platelet-derived growth factor receptor.

Masitinib had greater in vitro activity and selectivity against KIT than imatinib and also potently inhibits recombinant PDGFR [40]. In pancreatic cancer, a Phase II trial of masitinib associated with gemcitabine has showed encouraging results [72], leading to an ongoing Phase III trial. Recently, a Phase III study evaluating masitinib as a second-line treatment versus sunitinib in GIST [73] showed a survival benefit; thus, a Phase III trial is ongoing in first-line treatment of advanced or metastatic GIST versus imatinib. Motesanib has demonstrated significant antiangiogenic activity in preclinical data. After a Phase I study [74], a Phase II trial evaluating motesanib in the treatment of ovarian carcinoma was abruptly discontinued because of several cases of posterior reversible encephalopathy syndrome [75]. Recently, patients with squamous cell carcinoma were finally excluded of a Phase III trial evaluating motesanib in lung carcinomas because of limiting toxicities with 47% of serious adverse events, including fatal bleeding events [76]. So far, motesanib has shown modest activity in published data [77-79]. Nintedanib has been shown to consistently reduce the number of pericytes that carry the PDGFR in cell cultures [43] and could provide a possible solution to the observed resistance with other angiogenesis inhibitors [80]. Several Phase I and II trials have also reported its efficacy, alone or in combination, with different results in terms of tumor location, and others are ongoing. Recently, two Phase III studies evaluating nintedanib in combination with chemotherapy have shown OS and PFS improvement in non-small cell lung carcinoma after first-line chemotherapy respectively [81,82]. Orantinib is another tyrosine kinase, which has shown antiangiogenic activity in preclinical data. Despite toxicities reported in the Phase I study [83], orantinib is only under development in a Phase III trial with chemoembolization in patients with unresecable hepatocellular carcinoma. Telatinib has been developed in Phase I studies alone [84,85] or in combination with irinotecan and capecitabine without increased toxicities [86], or with bevacizumab in patients with advanced solid tumors, but this association was very toxic and the development was discontinued [87]. Only one Phase II trial is ongoing in patients with advanced gastric cancer. Tivozanib has shown in Phase I studies that its side effects are generally mild [88] with promising activity in a Phase I study in association with weekly paclitaxel in metastatic breast cancer [89] and in a Phase II trial in combination with

everolimus in colorectal cancer [90]. Recently, a randomized Phase III trial evaluating tivozanib versus sorafenib for firstline treatment of metastatic renal cell carcinoma showed improvement of PFS but not of OS [91]. Vatalanib has been largely developed few years ago, especially in colorectal cancer, with two Phase III randomized trials in combination with chemotherapy, but did not show improvement of outcome. There are also several Phase II trials evaluating its activity alone, in different tumor types but with poor outcomes. Currently, most trials evaluating valatinib are in combination with other treatments in Phase I and II trials, with chemotherapy, or with other targeted therapy.

Phase I and II trials of monoclonal antibodies which target PDGFR

3.2

Monoclonal antibodies have more specific targeting than tyrosine kinase inhibitors and have therefore usually less toxicity. In addition, they could lead to an immune response including complement-dependent cytotoxicity and antibody-dependent cellular cytotoxicity. Two antibodies targeting selectively PDGFRa, and no cross-reacting with PDGFRb, have been developed. In preclinical data, antibodies showed efficacy in tumor models dependent on PDGFRa signaling [92,93]. Olaratumab (IMC-3G3) is a fully human IgG1 mAb. In the Phase I trials, the most common adverse events were fatigue and infusion reaction, and olaratumab showed the preliminary antitumor activity [94]. Two Phase II trials evaluating olaratumab as monotherapy have been completed in GIST with or without PDGFRa mutations and in glioblastomas. In mouse models of ovarian tumors, high expression of PDGFRa was correlated with poor survival and olaratumab was only effective in combination with docetaxel, and thus could lead to sensitization to chemotherapy [95]. Therefore, olaratumab is specially developed in combination with other treatments and several trials are currently ongoing: a Phase II study evaluating olaratumab in association with carboplatin and paclitaxel in non-small cell lung carcinoma, a Phase II trial in association with liposomal doxorubicin in platinium-refractory ovarian cancer, a Phase I/II study in association with doxorubicin in soft tissue sarcomas, and a Phase II study in association with mitoxantrone in prostate cancer. Tovetumab (MEDI575) is a human IgG2 k mAb directed against PDGFRa. A Phase I trial reported fatigue and nausea


7

X

X

X

X

X X

X

Dasatinib


Fatigue Anorexia Pain Pyrexia Nausea/vomiting Diarrhea Cytolysis Pancreatis Stomatitis Dyspnea Hematologic Hypertension PRESS syndrome Thromboembolic Hemorrhage Palmoplantar syndrome Rash Pleural/Pericardic effusion Hypertryglyceridemia

Crenolanib

X

X

X X

X X

Dovitinib

X

X

X X

Lenvatinib

X

X

X X

X X

Linifanib

X

X

X X

X X

X X X

X

X

Motesanib

X

Masitinib

Table 4. Main adverse events reported with PDGFR targeted molecules under development.

X

X

X

X

Nilotinib

X X X

Nintedanib

X

X X X

Orantinib

X

X

X

X

X

X

Ponatinib


X

X X

Telatinib

X

X

X

Tivozanib

X

X

X

X

Vatalanib


as most frequent adverse events, but did not show evidence of tumor activity [96]. Two Phase II trials have been completed, in glioblastoma and in non-small cell lung carcinoma in combination with chemotherapy, but development has recently been discontinued.


4.

Conclusion

The PDFGR pathway has important functions in normal cell growth and, by overexpression or mutations, can lead to tumor development. Moreover PDGFR is expressed in the tumor microenvironment and could promote tumorigenesis. This review reports preclinical and clinical rationale for targeting PDGFR as anti-cancer therapy. Many agents targeting PDGFR are currently under development, most of them being non-selective tyrosine kinase inhibitors, whereas two are monoclonal antibodies. The status of development of theses different molecules is varied and in heterogeneous types of tumors. Nevertheless those therapies are not expected to have a major global anti-tumor effect and many could fail to become approved therapies. Improvement in the development of PDGFR inhibitors is needed. 5.

Expert opinion

This comprehensive report reviews the role of PDGFR pathway in tumorigenesis and the clinical development of different PDGFR inhibitors. PDGFR has been a target for the development of therapy in medicine since the 1990s and a bit of history may be interesting. At that time the objective was to develop molecules having the ability to inhibit PDGFR, EGFR and Protein Kinase C, which could be of use in treating fibrosis, atherosclerosis and restenosis. Different molecules emerged from this kinase inhibitors program, which was mostly dedicated to the treatment of cardiovascular disease. At the same time, BCR-ABL protein dysregulation was identified as the event leading to white blood cells proliferation in CML and existing compounds were screened for their ability to inhibit BCR-ABL [97]. This is how imatinib, initially developed as a PDGFR inhibitor, became the first targeted therapy in oncology. Furthermore in 2001 although imatinib had started its development in CML, a first case report evaluating imatinib in a patient with a GIST and showing a complete response was published [98]. After this publication, development of imatinib in GIST was initiated and only after PDGFR mutations in GIST were discovered. This historical example highlights that imatinib, the first targeted therapy, which was originally developed to inhibit PDGFR, has mainly been used in settings where the inhibition of PDGFR was not the target. In our opinion, the key messages of this review are the following. First, currently approved PDGFR inhibitors exist, but their targeting is not specific of PDGFR as they are multityrosine kinase inhibitors; their safety profile is now well determined and their toxicity is mostly manageable like for

imatinib. Second, despite preclinical data showing an important role of PDGFR in tumorigenesis, those PDGFR inhibitors are mostly prescribed not for their ability to inhibit PDGFR but because they target others tyrosine kinases mostly bcr-abl, kit, VEGFR; in fact the targeting of PDGFR in solid tumors is currently limited to GIST and DFSP. Third, only a limited number of molecules inhibiting PDGFR currently under development are indeed developed for their ability to inhibit PDGFR. So how those investigational therapies could be used as anti-cancer therapies remains unclear. A few rules that apply across all anti-cancer therapies should be reminded. 1) Having determined the target of the treatment is nowadays crucial for the development of anti-cancer therapeutics as predictive biomarkers of outcome are explored in large Phase III trials. This aspect is also a growing demand of regulators when approving an anti-cancer therapy. The key of success for a targeted therapy is the identification of an oncogenic driver as target. In lung cancer for example, EGFR inhibitors have significant efficacy in EGFR mutated lung cancers [99-101], because EGFR mutations are drivers of the disease [102]. In GIST, DFSP, and some leukemias, PDGFR is an important driver of the disease [103-105] and targeting PDGFR is effective. For these reasons, molecules and studies highlighted in Table 3 have a real chance to become anti-cancer therapies and this is particularly true when they are developed in tumors with unmet therapeutic needs such as glioblastomas. A new method, the study of the kinome (the activation of different tyrosine kinases) could help determine if the molecule under investigation is actually targeting the right target across all patients. In our institution a study is currently ongoing for patients treated with sunitinib for whom lymphocytes tyrosine kinases activity is determined prior and under treatment to determine the in vivo effect of the therapy. 2) A high selectivity in the targeting of an investigational agent can be wished or not but this has to be determined first. A highly selective agent is expected to have limited off-target adverse effects and a good safety profile and could therefore be developed either in a cancer with a specific activation of the pathway resulting from a limited number of mutations or in combination therapy. This point is crucial as two recent concepts are in favor of the inhibition of multiple pathways. The concept of synthetic lethality [106] implying the combination of two or more therapies leading to cancer-cell death whereas a single therapy would not, requires to have limited toxicity and non-overlapping toxicities. The concept of biological crosstalk refers to instances in which one or more components of one signal transduction pathway affects another signal


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transduction pathway. This can be achieved with shared components that can interact with either pathway. Those two concepts are important for the development of PDGFR inhibitors as for most tumor types the PDGFR pathway is not the only driver of tumor growth. Therefore the inhibition of PDGFR has to be associated to the inhibition of another pathway. This can be achieved with a multi-targeted tyrosine kinase inhibitor or with a very specific inhibitor associated to a specific inhibitor of another pathway. New engineered monoclonal antibodies appear to be useful in this setting. The drawback of a high selectivity could be an early mechanism of resistance from the cancer cells and therefore a limited efficacy when a wide targeting of tyrosine kinases and cellular pathways is more difficult to bypass. But of course clinically limiting toxicities are to be expected. 3) A sustained optimal exposition to the investigational therapy must be guaranteed to determine its efficacy. Recent publications have shown significant intra- and inter-individual variations in tyrosine kinase inhibitors bioavailability. Indeed, it has been demonstrated that exposure to sorafenib decreases over time [107] and that in some settings, dose escalation can restore efficacy [108,109]. For this reason the development of novel tyrosine kinase inhibitor must include an evaluation of the plasmatic exposure to the agent. This can be done by searching on-target adverse events for patients as it has been done for axitinib in a trial versus sorafenib in metastatic renal cell cancer [110]. But a more objective and patient-centered method is to simply determine the blood concentration. As a result, a trial comparing an approved therapy given at a flat dose to a novel molecule having the same molecular targets and safety profile but with blood drug monitoring to guarantee a sustained active exposure is expected to show significant benefit in antitumor activity with the challenger. But it has to be added that some particularities of PDGFR inhibition must be taken into account for the development PDGFR inhibitors. Because tumor cells and stroma cells associated to solid tumors express PDGFR, targeting PDGFR will affect both normal and cancer cells. In the PDGFR-negative tumor cell, the impact of an anti-PDGF drug that exclusively targets the stromal compartment can be studied. A preclinical study hypothesized that the overexpression of PDGF-BB in PDGFR-negative colorectal cancer and pancreatic cancer cells would result in increased pericyte coverage of endothelial cells in vivo, resulting in the tumor vasculature more resistant to antiangiogenic therapy. Treatment of PDGF-BB-overexpressing tumors with imatinib resulted in increased growth and

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decreased total pericyte content compared with those in untreated PDGF-BB-overexpressing tumors suggesting that PDGFR inhibitor agents should be used with caution when PDGFR is not the target on the cancer-cell itself [111]. Moreover the PDGFR pathway is closely entangled with other pathways, such as VEGFR, EGFR, FGFR, MET, and KIT. Thus, multikinase inhibitors could have interest in the approach of targeting PDGFR. An example in GISTs is that PDGFRa and KIT seem to be mutually exclusive and one mutated receptor can heterodimerize with the wild-type version of the other receptor, producing diverse signaling [103]. In this case, drugs such imatinib or sunitinib targeting both Kit and PDGFRa pathways would be more effective than monospecific targeted ones. Moreover, combination of anti-PDGFR and antiVEGFR inhibitors could have activity, because anti-PDGFR drug would induce ablation of pericytes leaving the tumor vessels accessible for anti-VEGFR drug. In preclinical data simultaneous inhibition of VEGFR and PDGFR with the kinase inhibitor SU6668 markedly sensitized xenograft tumor response to radiation therapy [112]. Interestingly, resistance to anti-VEGF treatment has been shown to involve PDGF-AA, -BB and --CC [113]. More agents targeting PDGFR are currently under development. Some seem to have the potential to become anticancer therapies given their targeting or their safety profile; however their development may prevent this from happening. In our opinion, whenever possible, studies should be based on a PDGFR over-activated pathway in cancer cells as preclinical studies indicate that PDGFR inhibition in PDGFR-negative tumor cells would result in tumor growth. Agents with less inter- and intra- individual variability in bioavailability should be preferred. Drug monitoring should be associated to the development to guarantee a sustained active exposure. A highly selective agent with limited toxicity, such as an mAb, could be important for combination therapies. If not highly selective, the agent should also target VEGFR as the effect is supposed to be synergistic with the inhibition of PDGFR. Finally current developers in highly specialized fields such as neuro-oncology should integrate in their development plan what has been already demonstrated across the oncology field during the last decade.

Declaration of interest The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.



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Affiliation Jennifer Arrondeau1, Olivier Huillard1, Camille Tlemsani1, Anatole Cessot1, Pascaline Boudou-Rouquette1, Benoit Blanchet2, Audrey Thomas-Schoemann2, Michel Vidal2, Jean-Marie Tigaud1, Jean-Philippe Durand1, Jerome Alexandre1 & Francois Goldwasser†1 † Author for correspondence 1 Paris Descartes University, Cochin Hospital, AP-HP, Medical Oncology Department, Angiogenesis Inhibitors Multidisciplinary Study Group (CERIA), Paris, France E-mail: [email protected] 2 Paris Descartes University, Cochin Hospital, AP-HP, Pharmacokinetics and Pharmacochemistry Unit, Angiogenesis Inhibitors Multidisciplinary Study Group (CERIA), Paris, France


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Early investigational therapeutics for gastrointestinal motility disorders: from animal studies to Phase II trials.

Novel investigational therapeutics for panic disorder.

Investigational drugs in Phase II clinical trials for the treatment of obesity: implications for future development of novel therapies.

PDGF receptors in tumor biology: prognostic and predictive potential.

Binding of GAP to activated PDGF receptors.

Investigational approaches to therapies for restless legs syndrome.

Novel class of potential therapeutics that target ricin retrograde translocation.

Novel investigational therapies for atopic dermatitis.

Phase II drugs that target cholinergic receptors for the treatment of overactive bladder.

DNA G-quadruplex and its potential as anticancer drug target.

Cyclin E1-CDK 2, a potential anticancer target.

Updates on Nutraceutical Sleep Therapeutics and Investigational Research.

Angiotensin II and noradrenaline increase PDGF-BB receptors and potentiate PDGF-BB stimulated DNA synthesis in vascular smooth muscle.

eIF2α, a potential target for stem cell-based therapies.

Development of synthetic lethality anticancer therapeutics.

Targeting Lipid Metabolic Reprogramming as Anticancer Therapeutics.

Cyclin-Dependent Kinase Inhibitors as Anticancer Therapeutics.

Clinically relevant anticancer polymer Paclitaxel therapeutics.

Do thymic malignancies respond to target therapies?

Validating the anticancer potential of carbon nanotube-based therapeutics through cell line testing.

Investigational therapies targeting the ErbB family in oesophagogastric cancer.

Phase II clinical trials on investigational drugs for the treatment of pancreatic cancers.

Investigational therapies for the treatment of spinal muscular atrophy.

Recommendations to Facilitate Expanded Access to Investigational Therapies for Seriously Ill Patients.