Platelet-derived growth factor receptors: A therapeutic target in solid tumors

Platelet-Derived Growth Factor Receptors: A Therapeutic Target in Solid Tumors

Daniel George

Platelet-derived growth factor (PDGF) was one of the

first polypeptide growth factors identified that signals

through a cell surface tyrosine kinase receptor

(PDGF-R) to stimulate various cellular functions in-

cluding growth, proliferation, and differentiation. Since

then, several related genes have been identified consti-

tuting a family of ligands (primarily PDGF A and B) and

their cognate receptors (PDGF-R (Y and p). To date,

PDGF expression has been shown in a number of dif-

ferent solid tumors, from glioblastomas to prostate

carcinomas. In these various tumor types, the biologic

role of PDGF signaling can vary from autocrine stimu-

lation of cancer cell growth to more subtle paracrine

interactions involving adjacent stroma and even angio-

genesis. The tyrosine kinase inhibitor imatinib mesy-

late (formerly ST157 I, [Gleevec]; Novartis Pharma-

ceuticals Corp, East Hanover, NJ) blocks activity of the

Bcr-Abl oncoprotein, and was recently approved for

several indications in the treatment of chronic myeloid

leukemia. lmatinib mesylate is also a potent inhibitor

of the PDGF-R kinase and is currently being evaluated

for the treatment of PDGF-responsive tumors such as

prostate cancer. More clinical trials that investigate

both established clinical endpoints of response and ben-

efit, as well as surrogate endpoints that may describe

the biologic significance of PDGF-R inhibition in vivo

are needed to expand the applications that target the

PDGF axis.

Semin Oncol 28 (suppf /7):27-33. Copyright 0 2001 by

W;B. Sounders Company.

A MONG THE fundamental biologic ques- tions underlying the concept of signal trans-

duction inhibition as anticancer therapy, none is more important than defining what constitutes an appropriate molecular target for inhibition. The definition of an ideal drug target continues to evolve with the introduction of drugs such as the tyrosine kinase inhibitor imatinib mesylate (formerly ST157 1, [Gleevec]; Novartis Pharmaceuti- cals Corp, East Hanover, NJ). Criteria include high tissue expression and a well-defined functional role in the pathogenesis of the tumor or its progression. Activation of the drug target must coincide with its function, and be specifically inhibited by a proposed therapeutic agent. The lack of an essential, nonredundant physiologic role in adult tissues is also important for drug safety, by allowing a reasonable therapeutic index. This pre- sentation will review the biology of platelet-de-

Seminars in Oncology, Vol 28, No 5. Suppl I7 (October), 2001: pp 27-33

rived growth factor receptor (PDGF-R) as a potential therapeutic target in solid tumors.

PLATELET-DERIVED GROWTH FACTOR

AND PLATELET-DERIVED GROWTH

FACTOR RECEPTOR

Receptor and Ligand Isoforrns

The various platelet-derived growth factor (PDGF) and PDGF-R isoforms compose a family of ligands and receptors. Platelet-derived growth factor is a 30-kd protein consisting of disulfide- bonded homodimers or heterodimers of A and B chains. The A and B chains are 60% homologous and show strict conservation of eight cysteine residues. These molecules are synthesized as higher molecular weight precursors that are subjected to proteolytic processing. All three combinations of subunits occur: AA, AB, and BB. The recently discovered PDGF C isoform occurs as a homodimer (PDGF CC); it is not known whether it can also form heterodimers with other PDGF chains.2 Platelet-derived growth factor also is des- ignated c&s. This proto-oncogene is the normal cellular homologue of the v-sis viral oncogene that causes simian sarcoma.

The PDGF-Rs occur as 01 and /3 homodimers or CY//~ heterodimers and belong to the protein ty rosine kinase family of receptors. The extracellular portions of these proteins are characterized by the presence of five immunoglobulin-like domains, created by regularly spaced disulfide bonds. The receptor chains share 30% similarity in their amino acid sequences. The intracellular portions of each receptor contain a conserved tyrosine ki-

From the Department of Medicine, Dana-Farber Cancer Insti- tute, Harvard Medical School, Boston, MA.

Dr George receives research grant support, consulting fees, and honoraria from TAP, Wyeth-Ayerst, and Nova& Pharmaceuti- cals. He is a consultant and/or equity holder for MedPanel and Veritasmedicine

Address reprint requests to Daniel George, MD, Dana-Farber Cancer Institute, 44 Binney St, Room D-1230, Boston, MA 02115.

Copyright 0 2001 by W.B. Saunders Company 0093-7754/01/2805-1706$35.00/O doi:l0.1053/sonc.2001.29185

27

28 DANIEL GEORGE

PDGF BB PDGF BB PDGFAB All PDGF

Fig I. Several PDGF isoforms bind to two related recep-

tors. The specificity in assembly of different dimeric receptor complexes and binding of PDGF isoforms is shown.

nase domain into which is inserted an interrupting sequence of approximately 100 amino acids. Sim- ilar “kinase inserts” are found in the homologous CSF-1 receptor and c-Kit receptors, and these are thought to be binding sites for the SH2 domains of substrates for these receptors.324 The 01 receptor can bind to all dimeric PDGF isoforms (AA, BB, AB and CC), whereas the p receptor chain prefe erentially binds to the B isoform (Fig 1).

Platelet-Deriwed Growth Factor-Mediated Signaling

After binding of the dimeric ligand to the extracellular portions of the two PDGF-R chains, a receptor homodimer or heterodimer is formed, allowing autophosphorylation of receptor tyrosine residues. Multiple SH2 domain-containing signal transduction molecules are recruited and bind to the phosphorylated receptors, thereby initiating various signaling pathways that ultimately lead to cell growth, changes in cell morphology, and pre- vention of apoptosis.s-7 The classical target cells for PDGF are fibroblasts and smooth muscle cells, but many other cell types express both receptors as well, including renal mesangial cells, testicular Leydig cells, neurons, Schwann cells, and retinal pigment epithelial cells of the central nervous system.8

Platelet-derived growth factor isoforms play an important role during embryonic development, particularly in the formation of connective tissue in various organs.9 In adult tissues, a primary function of PDGF is to stimulate wound healing, via chemotaxis and mitogenesis of fibroblasts, and se- cretion of extracellular matrix components. Plate- let-derived growth factor /3 receptors are expressed on capillary endothelial cells and PDGF has been shown to have proangiogenic effects.

Macrophages, T-lymphocytes, myeloid lineage hematopoietic cells, and mammary epithelium also express only the p isoform of receptor. Conversely, platelets, astrocytes, and liver sinusoidal epithelium express only PDGF (Y receptor. Finally, PDGF has been shown to have an important role in the control of the interstitial fluid pressure, most likely by stimulating interactions between connective tissue cells and the extracellular matrix.9

PLATELET-DERIVED GROWTH FACTOR IN CANCER

Autocrine Platelet-Deriwed Growth Factor Stimulation in Tumors

Whereas normal PDGF function is critical for normal embryonic development and adult ho- meostasis, as in wound healing, overactivity of the PDGF/PDGF-R axis has been implicated in several disorders characterized by excessive cell growth. These include fibrotic conditions, plaque formation during atherosclerosis, and certain ma- lignancies.9 Glial cells, fibroblasts, and smooth muscle cells are the normal physiologic targets of PDGF. Therefore, tumors derived from these cell types have been analyzed for autocrine stimulation, defined as signaling within a cell that both produces the ligand and expresses its receptor.

In the case of glioblastomas, a large fraction of analyzed tumors showed coexpression of PDGF CY receptor and PDGF A or B chains.iOJi Autocrine PDGF stimulation, in which the cell type secreting the ligand is also the target cell (Fig 2), is thought to contribute to the early transformation and progression of these tumors. For this reason imatinib

Tumor Cell

Fig 2. Coexpression of PDGF and PDGF-R in various types of human tumors is consistent with autocrine growth stimulation. Many common solid tumors display PDGF-producing tumor cells and PDGF-R-expressing stromal fibroblasts leading to a paracrine PDGF effect.

PDGF-R: A THERAPEUTIC TARGET IN SOLID TUMORS 29

Table I. Platelet-Derived Growth Factor Receptor Expression in Prostate Cancer

PDGF A PDGF B

PDGFR IY PDGFR a

Normal Epithelium

-

-

-

Normal StKliWl

-

-

PIN

+++/++ -

++/+

+

TUll%X Epithelium

+++/++ -

++ -

Tumor Stroma

++

fi -

NOTE: Intensity of labeling was scored as: -, none; +, low; + f, intermediate; + + f, high Abbreviation: PIN, prostatic intraepithelial neoplasia.

mesylate is being evaluated in clinical trials for treatment of adult and pediatric glioblastoma. Co- expression of PDGF and PDGF-Rs, suggestive of autocrine growth stimulation, also has been observed in various other types of human tumors including meningiomas, melanomas, neuroendo- crine tumors, ovarian cancer, pancreatic cancer, gastric cancer, lung cancer, and prostate cancer.9

Ligand-Independent Activation of Platelet-Derived Growth Factor Receptor in Tumors

The mechanisms of dysregulated PDGF and PDGF-R expression and function have not been fully elucidated. Overexpression of PDGF cr receptor in glioblastoma is associated with amplification of the PDGF-R gene. lo-l2 In chronic myelomonocytic leukemia, a chromosomal translocation gen- erates a fusion oncogene that encodes a ligand- independent, constitutively active form of the PDGF p receptor.isJ4

The transforming potential of the PDGF-R pathway and its mechanism are shown by the action of the E5 oncoprotein of bovine papilloma virus type 1. The E5 protein causes oligomerization of the PDGF p receptor, thereby inducing its con- stitutive activation in the absence of ligand.15

Paracrine Platelet-Derived Growth Factor Effects and Tumor Angiogenesis

Paracrine stimulation is essentially a hormonal effect occurring within a tissue. The many tissues that make up a solid tumor, stromal cells, blood vessels, and tumor parenchymal cells per se, function in a complex and interdependent way. Many common solid tumors, including colorectal adenocarcinoma, lung carcinomas, and breast carcinomas, contain both PDGF-producing cells and PDGF p receptor-expressing stromal fibroblasts

(Fig 2).9 In addition to promoting the growth of tumor stromal cells, PDGF-Rs on fibroblasts and pericytes may enhance tumor growth by regulating tumor interstitial fluid pressure and transcapillary transport.i6

Angiogenesis is critical for tumor growth and may be mediated either directly or indirectly. Di- rect angiogenic activity of the PDGF BB and PDGF /3 receptor isoforms involves recruitment and differentiation of pericytes, the cells that sta- bilize immature blood vessels and contribute to their functional integrity.17ais Indirect stimulation may be mediated via induction of other growth factors such as vascular endothelial growth factor.

PROSTATE CANCER AND PLATELET- DERIVED GROWTH FACTOR RECEPTOR

EXPRESSION

Ligund and Receptor Expression

Prostate cancer is the second most common cause of death from cancer in American men. The growth of normal prostate epithelium and primary prostate cancer is influenced by a number of growth factors, many of which function by binding to receptor tyrosine kinases. Immunohistochemi- cal analysis of PDGF A and B chains and PDGF 01 and p receptors in epithelial and stromal prostate tumor cells indicates that the PDGF A chain and the PDGF (Y receptor are expressed in these cells. In contrast, the normal cells surrounding the tumor lesions do not express PDGF A and PDGF (Y receptor (Table 1) .19,*0 Interestingly, these two proteins are also expressed in a precursor lesion in prostate cancer known as prostatic intraepithelial neoplasia. This observation suggests that de novo expression occurs early in the transformation pro- cess and may be causally related to it. The ubiq-

30 DANIEL GEORGE

Receptor Tyrosine Kinases Nonreceptor Tyrosine Kinases

PDGF-R a KDR

Eph I

DDR (TKT.Tyro IO) Tie- I

Tie-2 PDGF-R 6

EGF-R

Jak I FER

Lm Bmx

Brk YES

Jak 2 Abl

NOTE: Kinases are listed in descending order based on the

frequency with which they were isolated.

uitous, low levels of PDGF p receptor that were also seen are of uncertain significance.

Bone marrow is the predominant metastatic site for prostate cancer and bone marrow metastases account for the majority of prostate cancer mor- bidity and mortality. Chott et a12i assessed the role of growth factors and their cognate receptors in metastatic androgen-independent prostate cancer by reverse-transcriptase polymerase chain reaction in a series of bone marrow samples freshly isolated from patients with prostate cancer. Using degen- erate primers to amplify the conserved tyrosine kinase domain, several receptor and nonreceptor tyrosine kinases were identified in metastatic prostate cancer (Table 2). The PDGF (Y receptor and the Jak 1 kinase were present in the majority of samples. This assay was not quantitative and does not establish that PDGF-R is the most abundant kinase, only that it is the most frequently detected by this method. Immunohistochemistry of the bone marrow biopsies containing metastatic prostate cancer confirmed the presence of these kinases, and no staining was observed in the stroma, suggesting that expression was confined to the tumor cells.21

SUfOf Trial

These preclinical findings led to the first clinical trial of a putative PDGF-R antagonist in metastatic androgen-independent prostate cancer. The PDGF-R inhibitor SUlOl was evaluated in a multi-institutional, phase II trial in patients with hormone-refractory prostate cancer.22 The patient population included individuals with advanced-

stage disease, many of whom had already undergone a number of treatments including chemo- therapy.

The 39 evaluable patients continued on primary androgen ablation with luteinizing releasing hormone analogues or orchiectomy while SUlOl was administered as a weekly intravenous infusion fol- lowing a 4-day loading dose. This treatment regi- men achieved only modest overall clinical benefits. One explanation for the low response rate in the study is that the short halfelife of SUlOl produces only transient blockade of PDGF-mediated signaling, and that prolonged receptor inhibition may be necessary for clinical benefit. An- other possible limitation is that clinical response was evaluated solely by reduction in prostate- specific antigen (ISA) levels, with a positive response being defined as a 50% decline in PSA from pretreatment levels sustained over a q-week period.23

Immunohistochemistry for PDGF a! and 0 receptors was performed on fresh samples and ar- chived biopsies. This analysis showed a high level of PDGF-R expression on tumor epithelial cells that did not differ between the primary and metastatic sites, even for samples obtained from the same patients (Fig 3). These findings suggest that PDGF-Rs are consistently expressed during disease

C

Fig 3. lmmunohistochemical analysis of tumor samples from one patient. (A) Hematoxylin-eosin stain of bone marrow biopsy (magnification x 40). Focus of normal bone marrow elements on the right of the photograph, and focus of metastatic prostate adenocarcinoma on the left. (B) Immunoperox- idase stain for PDGF-R in bone marrow biopsy. Graded as 2+ in 75% to 100% of cells (magnification X 40). (C) Archival prostate needle biopsy (Hematoxylin-eosin stain, magnification X 20). (D) lmmunoperoxidase stain for PDGF-R in prostate biopsy. Graded as I + staining in IO% to 25% of cells (magnification X 20). (Reprinted with permission.**)


progression and that they may serve as an appropriate therapeutic target for all stages of disease.

IMATINIB MESYLATE AND PLATELET- DERIVED GROWTH FACTOR RECEPTOR

Imatinib mesylate is an inhibitor of the Abl and Bcr-Abl tyrosine kinases, the tyrosine kinase receptor for stem cell factor, c-Kit, and PDGFeR.24-26 Based on its preclinical activity against Bcr-Abl, imatinib mesylate has been evaluated in phase I and II clinical trials. It was recently approved by the US Food and Drug Administration for the treatment of patients with chronic myeloid leukemia in blast crisis, in accelerated phase, or in chronic phase after failure of interferon-alpha therapy. Clinical trial results indicated that imatinib mesylate is safe and well tolerated and pro- duced sustained remission in a majority of patients with chronic myeloid leukemia.27J-s The drug also showed remarkable efficacy in patients with metastatic gastrointestinal stromal tumor, in which the proto-oncogene c-kit is involved.z9-31

These results are very encouraging and suggest the use of imatinib mesylate against other potential molecular targets. In particular, imatinib mesylate may play a role in the treatment of pro- liferative diseases that involve abnormal PDGF-R activation such as hormone-refractory prostate cancer.

Phase II Trial of hatinib Mesyhte in Hormone- Refractory Prostate Cancer

With the goal of treating hormone-refractory prostate cancer patients with imatinib mesylate, a multi/institutional study encompassing eight cen- ters in the United States and Canada enrolled 40 patients. The trial was closed to accrual in May 2001. Patients received 400 mg of imatinib mesylate daily. The primary endpoint of the study was PSA response, with secondary endpoints of safety and time to disease progression; plasma vascular endothelial growth factor levels were also mea- sured. The results of this study are being finalized and will be available shortly.

While this study was designed as a preliminary evaluation of the efficacy of imatinib mesylate in patients with prostate cancer, it has several limitations. First, as in the previous SUlOl study, the patient population had very advanced prostate cancer. Many patients had previously undergone local therapy, and in all cases their disease had

progressed despite previous hormonal therapy. Im- portantly, the primary endpoint, PSA level, might not reflect the biological activity of imatinib mesylate in prostate cancer. Further, it also is not known whether the single 400-mg dose used is optimal for solid tumors like prostate cancer. Fi- nally, as an initial study it will not have the power to assess for cytostatic effects, including time to disease progression.

Pilot Study in Newly Diagnosed Patients

To address some of the limitations of this phase II trial, another pilot study has been initiated. This is a study of imatinib mesylate in newly diagnosed prostate cancer patients with localized, untreated disease before undergoing radical prostatectomy. These patients must have intermediate or high risk for disease relapse based on their PSA, Gleason score, and clinical stage (Fig 4).32

Before starting treatment, a baseline radiographic evaluation with positron emission tomog- raphy and magnetic resonance imaging will be performed. Biopsies also will be performed to ob- tain fresh tissue for molecular and gene expression assays. Patients will be treated for 6 weeks or more depending on their ability to tolerate the drug. Radiographic and biologic assays will be repeated

Baseline radiologic,

Biopsy MRI, MR Spectroscopy PET PSA, VEGF Genetic expression/ activation testing

Fig 4. Study design for a phase II trial for patients newly diagnosed with prostate cancer.

32 DANIEL GEORGE

after 6 weeks, at which time patients will undergo prostatectomy. They will receive imatinib mesylate up to the day of surgery to ascertain tissue concentration of drug. Gene expression profiling also will be evaluated at that time. Because PDGF plays an important role in both angiogenesis and wound healing, imatinib mesylate will be discon- tinued in the postoperative period.

The primary endpoint of this study is safety and tolerability. An important secondary objective is the pharmacodynamic assessment of the effects of imatinib mesylate in prostate cancer, using novel applications of technology in this setting. In particular, pathologic changes such as microvessel density and apoptotic indexes will be followed. Changes in disease volume will be evaluated by magnetic resonance imaging and 3D volumetrics. Magnetic resonance imaging spectroscopy and wa- ter diffusion will be used to measure apoptosis in viva, and dynamic flow magnetic resonance imaging will help to define a surrogate measure of angiogenesis. Prostate-specific antigen effects will be assessed.

An ambitious aspect of this project is to exam- ine gene expression alterations that occur in these patients. It will be technically challenging to get enough tissue for gene array analysis by needle biopsies, but it is clear that obtaining this infor- mation may be very useful to ascertain which patients are likely to benefit from imatinib mesylate.

CONCLUSION

Platelet-derived growth factor receptors repre- sent an attractive therapeutic target in prostate cancer as they are frequently expressed in these cancers. Their functional role in prostate cancer is still under intense investigation, but it is clear that they are specifically inhibited by the tyrosine kinase inhibitor imatinib mesylate. This inhibitor appears to have a favorable therapeutic index because PDGF-R is expressed at very specific devel- opmental stages (embryogenesis) and in response to stress (wound healing) in normal tissues.

Imatinib mesylate has been approved for the treatment of chronic myeloid leukemia and is now in clinical trials for patients with prostate cancer. Results from these trials should provide insight into the suitability of PDGF-R as a therapeutic target in prostate cancer. It is hoped that the development of gene expression profiling will help

to identify those patients most likely to respond to therapy. If pharmacodynamic assessments can gauge the effects of imatinib mesylate and identify patients likely to respond then future trials evalu- ating the clinical benefits of imatinib mesylate in selected patients may be considered.

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Platelet-derived growth factor receptors: A therapeutic target in solid tumors