Preoperative platelet-derived growth factor receptor inhibitor therapy combined with docetaxel and androgen ablation in high-risk localized prostate cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5141-5141
Author(s):  
P. Mathew ◽  
C. Pettaway ◽  
L. Pisters ◽  
D. Williams ◽  
P. Troncoso ◽  
...  
Keyword(s):  
Growth Factor ◽  
High Risk ◽  
Treatment Failure ◽  
Specific Antigen ◽  
Fluid Pressure ◽  
Growth Factor Receptor ◽  
Inhibitor Therapy ◽  
Platelet Derived Growth Factor ◽  
Gleason Grade ◽  
Androgen Ablation

5141 Background: Reduction in tumor interstitial fluid pressure with platelet-derived growth factor receptor (PDGFR) inhibitor therapy in experimental systems improves drug delivery and the therapeutic index of taxane chemotherapy (Pietras, Cancer Research, 2002). We hypothesized that PDGFR inhibitor therapy with imatinib mesylate combined with androgen ablation (AA) and docetaxel (D) induces pathological complete responses (pCR) in high-risk localized prostate adenocarcinoma (PC) prior to radical prostatectomy and pelvic lymph node dissection (RP). Methods: Thirty six men with PC ≥T2 disease or Gleason grade 8–10 or serum prostate-specific antigen (PSA) > 20 ng/ml or cT2b and PSA >10 ng/ml and Gleason 7 disease (AJCC, 1992), without radiological evidence of metastases, were planned to receive intramuscular leuprolide, imatinib 600mg orally daily, and weekly D 30 mg/m2 on D1, 8, 15, 22 q42 for three cycles (18 weeks) before RP [β (0.02, 1.98) prior on the possibility of pCR]. Unresectable pelvic nodal disease, post-operative PSA > 0.2 ng/ml or administration of post-operative radiation or AA were defined as treatment failure. Results: Between 6–03 and 9–04, 39 men were registered; median age 57 years (range, 44–71); 35 Caucasian, 2 Hispanic, 4 African-American. Risk factors included T3 disease (22/39), Gleason 8–10 disease (31/39), PSA > 20 ng/ml (12/39). Three men were ineligible or declined therapy; 29/36 (80%) received three cycles of therapy; 7/36 (20%) discontinued therapy related to toxicity. Grade 3–4 toxicity included rash (n=3), diarrhea (n=5), fatigue (n=3), neutropenia (n=2), hepatic (n=1). Severe or unexpected surgical complications were not encountered. No pCRs were defined; 15/36 (42%) have PSA < 0.2 ng/ml [12/36 (33%), <0.1 ng/ml] at 24 months and 13/36 (36%) met definition for treatment failure. Conclusions: The addition of the PDGFR inhibitor imatinib to pre-operative AA and D, although feasible, did not induce pCR in PC. [Table: see text]

Blockade of Platelet-Derived Growth Factor Receptor-Beta by CDP860, a Humanized, PEGylated di-Fab', Leads to Fluid Accumulation and Is Associated With Increased Tumor Vascularized Volume

2005 ◽  
Vol 23 (5) ◽  
pp. 973-981 ◽  
Author(s):  
G.C. Jayson ◽  
G.J.M. Parker ◽  
S. Mullamitha ◽  
J.W. Valle ◽  
M. Saunders ◽  
...  
Keyword(s):  
Growth Factor ◽  
Kinase Inhibitors ◽  
Performance Status ◽  
Fluid Pressure ◽  
Growth Factor Receptor ◽  
Fluid Retention ◽  
Platelet Derived Growth Factor ◽  
Fab Fragment ◽  
Beneficial Effects ◽  
Contrast Enhanced

Purpose CDP860 is an engineered Fab' fragment-polyethylene glycol conjugate, which binds to and blocks the activity of the beta-subunit of the platelet-derived growth factor receptor (PDGFR-β). Studies in animals have suggested that PDGFR-β inhibition reduces tumor interstitial fluid pressure, and thus increases the uptake of concomitantly administered drugs. The purpose of this study was to determine whether changes in tumor vascular parameters could be detected in humans, and to assess whether CDP860 would be likely to increase the uptake of a concurrently administered small molecule in future studies. Patients and Methods Patients with advanced ovarian or colorectal cancer and good performance status received intravenous infusions of CDP860 on days 0 and 28. Patients had serial dynamic contrast-enhanced magnetic resonance imaging studies to measure changes in tumor vascular parameters. Results Three of eight patients developed significant ascites, and seven of eight showed evidence of fluid retention. In some patients, the ratio of vascular volume to total tumor volume increased significantly (P < .001) within 24 hours following CDP860 administration, an effect suggestive of recruitment of previously non-functioning vessels. Conclusion These observations suggest that inhibition of PDGFR-β might improve delivery of a concurrently administered therapy. However, in cancer patients, further exploration of the dosing regimen of CDP860 is required to dissociate adverse effects from beneficial effects. The findings challenge the view that inhibition of PDGF alone is beneficial, and confirm that effects of PDGFR kinase inhibition mediate, to some extent, the fluid retention observed in patients treated with mixed tyrosine kinase inhibitors.

scholarly journals Relationship between platelet derived growth factor receptor‐β and Alzheimer’s biomarkers in a racially diverse, high‐risk cohort

2021 ◽  
Vol 17 (S5) ◽  
Author(s):  
Brittany Butts ◽  
Scott Miners ◽  
Patrick G. Kehoe ◽  
William T. Hu ◽  
Hanfeng Huang ◽  
...  
Keyword(s):  
Growth Factor ◽  
High Risk ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Racially Diverse ◽  
High Risk Cohort

scholarly journals 9p21 locus analysis in high-risk gastrointestinal stromal tumors characterized forc-kit and platelet-derived growth factor receptor α gene alterations

Cancer ◽  
2005 ◽  
Vol 104 (1) ◽  
pp. 159-169 ◽  
Author(s):  
Federica Perrone ◽  
Elena Tamborini ◽  
Gian Paolo Dagrada ◽  
Federica Colombo ◽  
Lorena Bonadiman ◽  
...  
Keyword(s):  
Growth Factor ◽  
High Risk ◽  
Gastrointestinal Stromal Tumors ◽  
Growth Factor Receptor ◽  
Platelet Derived Growth Factor ◽  
Stromal Tumors ◽  
9P21 Locus ◽  
Gene Alterations

Neoadjuvant trial of sunitinib malate and androgen ablation (ADT) in patients with localized prostate cancer (PCa) at high risk for recurrence.

2011 ◽  
Vol 29 (7_suppl) ◽  
pp. 143-143
Author(s):  
A. J. Zurita ◽  
J. F. Ward ◽  
J. C. Araujo ◽  
C. A. Pettaway ◽  
P. Dieringer ◽  
...  
Keyword(s):  
High Risk ◽  
Tyrosine Kinases ◽  
Combined Treatment ◽  
Pathologic Complete Response ◽  
Specific Antigen ◽  
Complete Response ◽  
Gleason Grade ◽  
Sunitinib Malate ◽  
Androgen Ablation ◽  
Pdgf Signaling

143 Background: Presurgical ADT does not improve long-term outcomes in patients (pts) with high-risk localized PCa. Since the VEGF and PDGF signaling pathways have been implicated in PCa progression, and ADT results in endothelial cell apoptosis in the prostate by a VEGF-mediated mechanism, we hypothesized that combined treatment with sunitinib malate (SU), an oral inhibitor of the tyrosine kinases of VEGFR and PDGFR, might improve the efficacy of ADT in this pt population. Methods: Pts with no radiological evidence of metastases and either PCa ≥ clinical (c)T3 disease or Gleason grade 8-10 or serum prostate-specific antigen (PSA) ≥ 20 ng/mL or cT2b-c and Gleason 7 and PSA ≥10 ng/mL (AJCC, 1992), received i.m. leuprolide and oral SU for three 30-day cycles followed by surgery. SU was administered continuously at 37.5 mg daily (25 mg daily in the initial 6 pts). The primary endpoint of this phase II trial was rate of pathologic complete response (pCR). Secondary endpoints included safety and time to progression (TTP). Unresectable pelvic nodal disease, confirmed post-operative PSA ≥ 0.2 ng/mL, or administration of post-operative radiation or ADT, defined treatment failure. Results: Forty-four pts completed accrual, with a median age of 58 years (range 47-72); 34 Caucasian, 5 African-American, 4 Hispanic, and 1 Indian. High-risk criteria included cT3 (24/44), Gleason 8-10 (30/44), PSA ≥ 20 ng/mL (16/44). Two men were ineligible/declined therapy and one postponed surgery. No grade 4 toxicities or related discontinuations were observed. Thirty-five pts completed 3 months on 37.5 mg daily SU plus ADT and surgery with no unexpected complications. Of these, 2 pts experienced a pCR. Twenty (57%) pts have failed treatment or died, with a median TTP 27 months (95% CI: 12 – not estimable). The median follow-up of the remaining event-free pts is 35 months (range 23-41). Conclusions: The 3-months preoperative combination of SU and ADT is safe and well tolerated in pts with high-risk primary PCa. We observed 2 complete remissions in 35 patients. Ongoing characterization of molecular changes in the epithelial and stromal compartments will help understand the mechanisms of SU activity in PCa. [Table: see text]

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