Oncology Intelligence



PDGF is a growth factor family RTK that plays a role in embryonic development, cell proliferation, cell migration, and angiogenesis.(1, 2) Proteins in PDGF family include: FIGF, PDGFA; PDGFB; PDGFC; PDGFD, PGF, VEGF; VEGF41; VEGFB; and VEGFC.(1)PDGFs are mitogenic during early developmental stages, driving the proliferation of undifferentiated mesenchyme and some progenitor populations. During later maturation stages, PDGF signalling has been implicated in tissue remodeling and cellular differentiation, and in inductive events involved in patterning and morphogenesis. PDGF is a required element in cellular division for fibroblasts.(2) PDGFs allow a cell to skip the G1 checkpoints. PDGF regulates proliferation of oligodendrocyte progenitor cells.(1) Synthesis of PDGF occurs due to external stimuli such as thrombin, low oxygen tension, or other cytokines and growth factors.(1, 2)
PDGF is a dimeric glycoprotein composed of two A (-AA) or two B (-BB) chains or a combination of the two (-AB). There are five different isoforms of PDGF that activate cellular response through two different receptors. Known ligands include A (PDGFA), B (PDGFB), C (PDGFC), and D (PDGFD), and an AB heterodimer and receptors α (PDGFRA) and β(PDGFRB). The α type binds to PDGF-AA, PDGF-BB and PDGF-AB, whereas the β type PDGFR binds with high affinity to PDGF-BB and PDGF-AB. PDGF binds to PDGFRs ligand binding pocket located within the second and third Ig domains. Upon activation by PDGF, these receptors dimerize, bind cofactors, and activate signal transduction.(1) For example, the PI3K pathway is activated by PDGF.(3)

Marketed Drugs
Generic Code Old Code Brand Company Indication trials
imatinib STI571 CGP57148, CTI571, QTI571, ST571 Gleevec, Glivec, Luckyvec Novartis Mkt: GIST, ALL, CML, dermatofibrosarcoma, MDS, mastocytosis; P3: PC, BC; P2: AML, mesothelioma, GBM, lung, SCLC, melanoma, ovarian, peritoneal, meningioma, uterine, MDS, chordoma, cholangiocellular, HNN, NSCLC, brain, CNS, MM, CRC, solid, NET; P1/2: sarcoma; P1: leukemia trials
nilotinib AMN107 Tasigna Novartis Mkt: CML; P3: GIST, melanoma; P2: ALL; P1: CRC, HNN, chordoma, solid trials
pazopanib GW786034 SB-786034 Votrient, Armala, Patorma GSK Mkt: sarcoma, RCC; P3: ovarian; P2: brain, BC, cervical, endometrial, HCC, NSCLC, mesothelioma, MM, nasopharyngeal, neuroendocrine, PC, thyroid, urothelial, CNS, gastric, HNN, melanoma, bladder, NET; P1: CRC, solid, lymphoma, SCLC trials
radotinib Supect Il-Yang Mkt (Korea): CML; P3: CML trials
sorafenib BAY 43-9006 Nexavar Bayer Mkt: HCC, thyroid, RCC, angiosarcoma; P3: BC, NSCLC, pancreatic, melanoma; P2: ovarian, GIST, bladder, sarcoma, GBM, CRC, PC, MM, cervical, esophageal, HNN, lymphoma, leukemia; P1: glioma trials
sunitinib SU011248 PNU 290940 Sutent Pfizer Mkt: RCC, GIST; P3: NSCLC, BC, pancreatic, CRC, HCC, PC; P2: bladder, biliary, astrocytoma, CNS, ovary, thyroid, sarcoma, melanoma, MM, NET, lymphoma, leukemia, HNN, esophageal, cervical, bladder, stomach, endometrial trials
Trial Drugs/Interactions
Generic Code Old Code Brand Company Indication trials
amuvatinib MP470 Astex P2: SCLC; P1: solid trials
axitinib AG-013736 Inlyta Pfizer Mkt: RCC; P3: pancreatic; P2: solid, GBM, CRC, adrenal, HNN, HCC, thyroid, melanoma, PC, NET, BC, MDS, AML, NSCLC; P1/2: mesothelioma; P1: gastric trials
crenolanib CP-868-596 ARO-002 Pfizer P3: AML; P2: glioma, GIST, AML, ovarian; P1: solid trials
dovitinib TKI258 CHI258 Novartis P3: RCC; P2/3: solid; P2: HCC, CRC, pancreatic, bladder, GBM, GIST, mesothelioma, melanoma, PC, thyroid, BC, urothelial, NSCLC; P1: AML trials
famitinib SHR1020 Jiangsu P3: CRC; P2: GIST, NSCLC, pancreatic, neuroendocrine, BC, nasopharyngeal; P1: solid trials
lestaurtinib CEP-701 KT 5555, SPM 924 Cephalon P3: leukemia, ALL; P2: PC, myeloma (terminated), AML; P1: neuroblastoma trials
midostaurin PKC412 CGP 41251 Novartis P3: AML; P2: MDS, mast cell leukemia, lymphoma, ALL; P1: rectal trials
flumatinib Jiangsu P3: CML trials
linifanib ABT-869 RG3635 Abbvie P3: HCC; P2: NSCLC,CRC, BC, RCC; P1: solid trials
motesanib AMG 706 Takeda, Amgen P3: NSCLC (failed); P2: thyroid, BC (failed), GIST (failed), ovarian (failed), fallopian (failed), neuroendocrine, solid; P1: lymphoma, CRC, pancreatic trials
nintedanib BIBF1120 Vargatef, Ofev Boehringer Ingelheim Mkt: NSCLC; P3: ovarian, CRC; P2: HCC, PC, ovarian, SCLC, glioma, GBM, endormetrial, fallopian, methothelioma, esophaphageal, thyroid; P1/2: AML, P1: solid, MM trials
olaratumab LY3012207 IMC3G3 Eli Lilly P2: NSCLC; P1: solid trials
orantinib TSU-68 SU6668 Taiho P3: HCC (terminated; primary endpoint of overall survival was not met); P1: BC, CRC, gastric, RCC, solid, NCSCL (Japan) trials
telatinib BAY 57-9352 Bayer Filed/orphan status approved: P2: gastric cancer (one trial) trials
vatalanib PTK787 ZK222584 Bayer P3: CRC; P2: MM, leukemia, brain, CNS, BC, NSCLC, NET, lymphoma, melanoma, mesothelioma, MDS, pancreatic, PC, cervical, solid trials
CM082 X-82 Challenge; Tyrogenex P1/2: pancreatic; P1: solid trials
TAK-593 Takeda P1: solid trials
Failed Drugs
Generic Code Old Code Brand Company Indication trials
JI-101 CGI-1842 Roche terminated: P1/2: neuroendocrine, ovarian, CRC, solid trials
MEDI-575 MedImmune terminated; P2: GBM; P1: solid trials
RG1530 Roche Last trial started in 2007; P1: solid trials
SU014813 Pfizer Last new trial started in 2006; P2: BC; P1: solid trials
XL820 Exelixis; GSK Last new trial started in 2007; P2: GIST; P1: solid trials
IMC-3G3 noncorporate P2: brain, CNS trials

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1. Beneke S, Alvarez-Gonzalez R, Brkle A. Comparative characterisation of poly (ADP-ribose) polymerase-1 from two mammalian species with different life span. Experimental gerontology. 2000;35(8):989-1002.

2. Alvarez RH, Kantarjian HM, Cortes JE, editors. Biology of platelet-derived growth factor and its involvement in disease. Mayo Clinic Proceedings; 2006: Elsevier.

3. Kratchmarova I, Blagoev B, Haack-Sorensen M, Kassem M, Mann M. Mechanism of divergent growth factor effects in mesenchymal stem cell differentiation. Science. 2005;308(5727):1472-7.

4. PDGF. [cited]; Available from:

Thursday, July 28, 2016 7:56 AM|Sizemore, G., Mathur, A., Thies, K., Bolyard, C., Sizemore, S., Kladney, R., Trimboli, A., Kaur, B., Leone, G., Ostrowski, M.|Cancer Research recent issues|Labels: PDGF, breast cancer
A role for the tumor microenvironment (TME) in cancer progression is irrefutable and our laboratory has been at the forefront of this field providing evidence for both tumor suppressive and oncogenic roles of the TME. The PDGF pathway is an exemplar for the study of tumor-stroma interaction as PDGF receptors (PDGFR) are frequently expressed in the fibroblasts and pericytes within the tumor-associated stroma of epithelial tumors including breast cancer. In contrast, PDGF ligands are expressed by the epithelial tumor cells themselves. However, beyond a few descriptive studies, the role of interactive PDGFRβ signaling in the TME during breast cancer initiation, progression and metastases is not understood. This can be attributed in part to limited in vivo models to study the complex TME, especially for breast cancer associated metastases. To overcome this limitation, we have established a transgenic knock-in mouse model that expresses constitutively active PDGFRβ in the stroma of the mammary gland as well in the lung and the brain, two common sites of metastatic breast cancer dissemination. We have found that these mice develop mammary gland hyperplasia highlighting the importance of PDGFRβ in the TME in driving mammary epithelial cell growth. To test whether activation of mutant PDGFRβ in either the lung or the brain increases metastatic growth at either site, two experimental metastases assays were performed: (1) tail vein and (2) intracranial injections to test for lung and brain metastatic outgrowth, respectively. Tail vein injection of the non-metastatic murine mammary cancer cell line DB7 cells led to pronounced lung metastases in PDGFRβ knock-in mice in less than 4 weeks. No macrometastases were seen in the control at this same time point. Similar to the surge in lung metastasis, intracranial injection of DB7 cells led to an increase in tumor growth in brains of the mutant versus wild type controls, revealing an important role for PDGFRβ signaling in the breast cancer metastatic microenvironment. In addition, knockdown of PDGF-B in mammary cancer cells represses intracranial growth in wild type animals. Combined these data support a role for PDGFRβ signaling in the breast cancer metastatic microenvironment. Ongoing investigation is aimed to delineate how activated PDGF-B to PDGFRβ signaling primes the metastatic niche.Citation Format: Gina Sizemore, Anisha Mathur, Katie Thies, Chelsea Bolyard, Steven Sizemore, Raleigh Kladney, Anthony Trimboli, Balveen Kaur, Gustavo Leone, Michael Ostrowski. Platelet-derived growth factor receptor-β (PDGFRβ) in the breast metastatic tumor microenvironment. [abstract]. In: Proceedings of the AACR Special Conference: Function of Tumor Microenvironment in Cancer Progression; 2016 Jan 7–10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2016;76(15 Suppl):Abstract nr C28.
Thursday, July 28, 2016 1:46 PM|Onclive Colorectal Cancer Articles|Labels: FGFR, PDGF, VEGF, CRC, clinical trial
Axel Grothey, MD, discusses both the LUME-1 and LUME-2 trials, the differences between left and right tumors in colorectal cancer, and how that information could potentially be used in diagnosis and treatment.
Wednesday, February 17, 2016 7:36 AM|Expert Review of Anticancer Therapy|MedWorm: Non-Small Cell Lung Cancer|Comments|Labels: FGFR, PDGF, VEGF, lung cancer
Authors: Syrios J, Nintos G, Georgoulias V Abstract Non-small lung cancer (NSCLC) is a lethal malignancy when diagnosed in advanced stage. The evolution of chemotherapy and the development of agents targeting certain molecular pathways involved in tumor progression improved the prognosis. Nintedanib is a new tyrosine kinase inhibitor, which exerts its activity by blocking VEGF, FGF and PDGF receptors and inhibits the angiogenic signaling by preventing receptor dimerization. Several Phase I and II studies proved its safety and efficacy in diverse solid tumors. In patients with advanced NSCLC, the administration of nintedanib may offer an additional chemotherapy benefit in terms of response rate, progression-free survival and overall survival particularly in patients with adenocarcin...
Wednesday, June 1, 2016 8:50 PM|Peter Stopfer|JournalTOCs API - Journal of Clinical Pharmacology (94 articles)|Labels: FGFR, PDGF, VEGF

Pharmacokinetic properties of nintedanib in healthy volunteers and patients with advanced cancer
Claudia Dallinger Dirk Trommeshauser, Kristell Marzin, Andre Liesener, Rolf Kaiser, Peter Stopfer
Journal of Clinical Pharmacology, Vol. , No. (2016) pp. -
Nintedanib, a triple angiokinase inhibitor, has undergone clinical investigation for the treatment of solid tumors and idiopathic pulmonary fibrosis. Nintedanib (Vargatef®) plus docetaxel is approved in the EU for the treatment of patients with adenocarcinoma NSCLC after first‐line chemotherapy, and as monotherapy (Ofev®) in the USA and EU for the treatment of patients with idiopathic pulmonary fibrosis. Pharmacokinetics (PK) of nintedanib after oral single‐ and multiple‐doses and intravenous (i.v.) administration were assessed using three datasets: (1) an absolute bioavailability trial that enrolled 30 healthy volunteers; (2) a pooled data analysis of four studies that enrolled a total of 113 healthy volunteers; (3) a pooled data analysis of four studies that enrolled a total of 149 patients with advanced cancer. In the absolute bioavailability trial of healthy volunteers, nintedanib showed a high total clearance (geometric mean: 1390 mL/min) and a high volume of distribution at steady state (Vss = 1050 L). Urinary excretion of i.v. nintedanib was about 1% of dose; renal clearance was about 20 mL/min and therefore negligible. There was no deviation from dose proportionality after i.v. administration in the dose range tested. Absolute bioavailability of oral nintedanib (100 mg capsule) relative to i.v. dosing (4‐hour infusion, 6 mg) was slightly below 5%. Nintedanib was quickly absorbed after oral administration. It underwent rapid and extensive first‐pass metabolism and followed at least biphasic disposition kinetics. In advanced cancer patients, steady state was reached at the latest at 7 days for twice‐daily dosing. Nintedanib's PK was time‐independent; accumulation after repeated administration was negligible. This article is protected by copyright. All rights reserved

Wednesday, September 14, 2016 3:30 AM|Takuji Okusaka, Taiga Otsuka, Hideki Ueno, Shuichi Mitsunaga, Rie Sugimoto, Kei Muro, Isao Saito, Yusuke Tadayasu, Kohei Inoue, Arsene-Bienvenu Loembé, Masafumi Ikeda|Cancer Science|Labels: FGFR, PDGF, VEGF, liver cancer, clinical trial
This phase I, dose-escalation study evaluated the safety, preliminary efficacy and pharmacokinetics of nintedanib, a triple angiokinase inhibitor, in Japanese patients with advanced hepatocellular carcinoma and mild/moderate liver impairment. Thirty patients with unresectable hepatocellular carcinoma were enrolled to groups, depending on whether liver impairment was mild (Group I: AST and ALT ≤2x ULN and Child–Pugh score 5 [n=14] or 6 [n=2]) or moderate (Group II: Child–Pugh score 5–6 and AST or ALT >2x to ≤5x ULN [n=7] or Child–Pugh score 7 [n=7]); 22 patients had prior sorafenib treatment. Nintedanib was administered twice daily in 28-day cycles until disease progression or unacceptable adverse events, starting at 150 mg (Group I) or 100 mg (Group II) and escalating to 200 mg. The primary objective was to define the maximum tolerated dose based on occurrence of dose-limiting toxicities during Cycle 1 (Grade ≥3 non-hematological and Grade 4 hematological adverse events). No dose-limiting toxicities were reported during Cycle 1 and the maximum tolerated dose for both groups was 200 mg twice daily. The most frequent adverse events were gastrointestinal (diarrhea, nausea, vomiting, decreased appetite). No patients discontinued nintedanib due to adverse events; 31% of Group I and 21% of Group II had dose reductions. Median time to progression was 2.8 months (95% CI 1.05–5.52) for Group I and 3.2 months (95% CI 0.95–6.70) for Group II. Nintedanib showed a manageable safety profile and efficacy signals, including in patients previously treated with sorafenib. ClinicalTrials. gov NCT01594125; 1199.120 This article is protected by copyright. All rights reserved.
Thursday, April 28, 2016 9:59 AM|CUMPĂNAS, A. A., CIMPEAN, A. M., FERICIAN, O., CEAUSU, R. A., SARB, S., BARBOS, V., DEMA, A., RAICA, M.|Anticancer Research recent issues|Labels: PDGF, kidney cancer

Background/Aim: Studies developed in the field of platelet-derived growth factors/platelet-derived growth factor receptors (PDGFs/PDGFRs) inhibition have focused on the therapeutic effects on tumor cells, neglecting their potential effects on tumor blood vessels. We herein propose a differential and critic assessment of platelet-derived growth factor B (PDGF-B) and platelet-derived growth factor receptor β (PDGFRβ) in renal cell carcinoma, correlated with the four main vascular patterns previously reported by our team. Materials and Methods: PDGF-B and PDGFRβ were evaluated on 50 archival paraffin embedded specimens related to vascular endothelial growth factor (VEGF), its inhibitory isoform VEGF165b and vascular patterns. Results and Conclusion: Our results support the involvement of VEGF165b in the phosphorylation of PDGFRβ with an inhibitory effect on endothelial proliferation and migration. The simultaneous action of PDGF-B/PDGFRβ and VEGF165b on the same type of receptor may explain the resistance to antiangiogenic therapy, which depends on the degree of modulation of PDGFRβ phosphorylation.