In a world of few frontiers left for mankind to explore, cancer research represents a new kind that humanity is travailing to conquer. The journey is fraught with difficulties—false starts, false hopes, and failure. However, the efforts of medical researchers globally, in concert and singular in focus, give us confidence that it is a matter of time before we yet again achieve what was once deemed impossible.
Cancer research is not a single entity; rather, it is the sum total of individual studies covering all aspects of human biology. In this article, we will be discussing the role of platelet-derived growth factors (PDGFs) and PDGF receptors (PDGFRs) in cancer research today.
A Highly Relevant Signaling Pathway
PDGFs and PDGFRs are highly relevant in cancer studies because they are known to be expressed in a number of tumors. Examples include gastrointestinal stromal tumor (GIST), non-small cell lung cancer, hepatocellular carcinoma, and medullary thyroid carcinoma.
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Under normal circumstances, PDGF promotes the proliferation, migration, and survival of mesenchymal cells. However, an aberrant PDGF/PDGFR signaling pathway is responsible for triggering a series of metabolic responses that cause the cancer to grow. Its role in tumorigenesis is well-documented in the medical literature.
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In a recently published review article, Zou and colleagues wrote, “The PDGF/PDGFR signaling pathway is considered an important receptor tyrosine kinase (RTK) pathway that promotes the proliferation, invasion, metastasis, and angiogenesis of tumor cells.”
“Dysfunction of PDGF signaling has been observed in a wide array of pathological conditions, such as cancer, fibrosis, neurological conditions and atherosclerosis,” Papadopoulos and Lennartsson wrote in another published review. “Reported abnormalities of the PDGF pathway include overexpression or amplification of PDGF receptors (PDGFRs), gain of function point mutations or activating chromosomal translocations.”
The Role of Tyrosine Kinase Inhibitors
The recognition of the role of the PDGF/PDGFR pathway in cancer pathophysiology makes it an attractive therapeutic target, and PDGFR inhibitors are widely used today. Imatinib, for example, is a multitarget small molecule inhibitor of tyrosine kinase, and its main mechanism is targeting PDGF/PDGFR-β signaling. It was the first drug of its kind to be approved for use in the US and has demonstrated promise in treating cancers such as leukemia, GIST, neuroblastoma, and glioblastoma.
Studies indicate that about two-thirds of GIST patients have the c-Kit mutation, while about 5% to 10% of patients have platelet-derived PDGFRα mutations in RTKs. Studies investigating the potency of imatinib in treating GIST demonstrate promising results: imatinib provides for a small but sustained overall survival benefit for high-risk GIST patients. Its efficacy as a GIST drug can be in part predicted based on the patient’s Kit and PDGFRα mutation status.
The antitumor properties of imatinib, however, are less pronounced in some in vitro and in vivo studies. For example, studies demonstrate that the combination of imatinib and letrozole results in limited efficacy in patients diagnosed with hormone receptor-positive metastatic breast cancer expressing PDGFR-β or c-Kit. In addition, imatinib has no efficacy in treating glioblastoma multiforme, according to clinical studies.
Zou et al offered 3 reasons why the clinical picture of imatinib is mixed:
- It results in chemical resistance by increasing ATP binding cassette subfamily B member 1 (ABCB1) expression in some cancer cells.
- It apparently demonstrates stronger therapeutic potential in the stomach compared to nongastric environments.
- It promotes platelet apoptosis and can induce platelet abnormalities, blunting its tumor-suppressive effects.
The Potential of Monoclonal Antibodies
Another class of drugs that have been developed to target PDGFR are monoclonal antibodies that have the ability to inactivate them. For example, PDGFR-β-blocking antibodies were used in a clinical study by Jo et al on a model of corneal and choroidal neovascularization. The results? Papadopoulos and Lennartsson wrote, “As a combination therapy with anti-vascular endothelial growth factor (VEGF) DNA aptamer, it was more effective at causing vessel regression at the sites of neovascular growth than anti-VEGF-A treatment alone.”
A relatively successful drug is olaratumab, which is a fully human immunoglobulin G1 with a high affinity for PDGFRα. Studies have demonstrated that when used in combination with docetaxel and gemcitabine, olaratumab has an excellent ability to block the growth of PDGFRα-expressing tumors. When used with doxorubicin, it is effective in treating adult soft-tissue sarcoma.
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However, olaratumab is not effective in all types of cancers. For example, studies demonstrate that it is relatively ineffective in treating prostate cancer, ovarian cancer, advanced non-small cell lung cancer, and metastatic GIST.
The Broader Picture
The problem with targeting any single pathway in cancerogenesis is that it affects the tumor microenvironment as a whole and may lead to consequences that are not immediately obvious.
Papadopoulos and Lennartsson wrote, “Due to the complex crosstalk within the tumor and variability of tumor types, it is often not possible to estimate how much of the therapeutic effect is derived from directly targeting the tumor cells or from affecting the tumor microenvironment.”
Ongoing clinical studies continue to shed light on the PDGF/PDGFR axis and the implications of targeting it via various therapeutic strategies. Clarification on why some drugs succeed and others fail will help scientists develop better anti-cancer therapies in the future.
References
Zou X, Tang XY, Qu ZY, et al. Targeting the PDGF/PDGFR signaling pathway for cancer therapy: a review. Int J Biol Macromol. 2022;202:539-557. doi:10.1016/j.ijbiomac.2022.01.113
Papadopoulos N, Lennartsson J. The PDGF/PDGFR pathway as a drug target. Mol Aspects Med. 2018;62:75-88. doi:10.1016/j.mam.2017.11.007
Jo N, Mailhos C, Ju M, et al. Inhibition of platelet-derived growth factor B signaling enhances the efficacy of anti-vascular endothelial growth factor therapy in multiple models of ocular neovascularization. Am J Pathol. 2006;168(6):2036-2053. doi:10.2353/ajpath.2006.050588
