scholarly journals Bridging Sunitinib Exposure to Time‐to‐Tumor Progression in Hepatocellular Carcinoma Patients With Mathematical Modeling of an Angiogenic Biomarker

2016 ◽  
Vol 5 (6) ◽  
pp. 297-304 ◽  
Author(s):  
S Ait‐Oudhia ◽  
DE Mager ◽  
V Pokuri ◽  
G Tomaszewski ◽  
A Groman ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Hepatocellular Carcinoma ◽  
Tumor Progression ◽  
Time To Tumor Progression

Bridging sunitinib exposure to time-to-tumor progression in hepatocellular carcinoma patients with mathematical modeling of an angiogenic biomarker.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. e14690-e14690
Author(s):  
Sihem Ait-Oudhia ◽  
Donald E. Mager ◽  
Garin Tomaszewski ◽  
Adrienne E. Groman ◽  
Patricia D. Zagst ◽  
...  
Keyword(s):  
Mathematical Modeling ◽  
Hepatocellular Carcinoma ◽  
Tumor Growth ◽  
Tumor Progression ◽  
Time Course ◽  
Drug Exposure ◽  
Plasma Concentrations ◽  
Target Range ◽  
Tumor Growth Inhibition ◽  
Time To Tumor Progression

e14690 Background: Hepatocellular carcinoma (HCC) is the most common primary liver malignancy with 250,000 new annual cases in the US. Sunitinib (SU), an oral tyrosine kinase inhibitor, inhibits tumor cell proliferation, selectively binds to the angiogenesis biomarker (VEGFR2), and is metabolized to an equipotent metabolite (SU12662). The objective of this study is to utilize mathematical modeling to bridge drug exposure and VEGFR2 dynamics to tumor growth inhibition (TGI) and time-to-tumor progression (TTP). Methods: Plasma concentrations of SU, SU12662, and VEGFR2, and tumor growth and TTP measurements were obtained from a phase-II study in 16 patients with unresectable HCC. SU was administered at 37.5 mg daily 7-days prior to chemoembolization, then on days 15-35. A MAP Bayesian approach was utilized to model SU and SU12662 pharmacokinetics (PK), both captured with a two-compartment model including linear clearances. Inhibition of VEGFR2 production was mediated by predicted active unbound concentrations (ACub) of SU and SU12662. VEGFR2 concentrations were the driver for TGI. The TTP probability was modeled with exponential hazard function dependent on a time varying covariate -the difference in VEGFR2 concentration from its baseline (ΔVEGFR2). Results: Drug and metabolite clearances (CLd, CLm) were estimated at 30.3 (19, %RSE) and 19.7L/h (14). Their volumes of distribution (Vd, Vm) were 1,780 (39) and 1840L (25). SU exposure was within target range for VEGFR2 inhibition. VEGFR2 half-life in plasma was calculated at 4h. The slope (α) for ACub effect on VEGFR2 production was 0.77(µg/mL)-1 (14). The ΔVEGFR2 effect on TGI was assumed maximal, whereas its potency (ΔIC50) was estimated at 1.83x10-2µg/mL (41). The between-subjects variabilities were 37.4, 51, 44.7, 64.8, 21, and 36% for CLd, CLm, Vd, Vm, α, and ΔIC50. The median observed tumor size baseline was 91 mm3. The simulated mean TTP was 7 months. Conclusions: The time-course of SU, SU12662, and VEGFR2 were captured well with final PK/pharmacodynamic models. VEGFR2 profiles successfully linked drug exposure to TGI and TTP. This model may serve as a general platform for the dynamics of anti-angiogenic drugs.

The correlation between the decrease of intratumoral arterial enhancement and time-to-tumor progression in patients with hepatocellular carcinoma treated with sorafenib.

2011 ◽  
Vol 29 (4_suppl) ◽  
pp. 167-167
Author(s):  
Y. Kojima ◽  
S. Mitsunaga ◽  
M. Ikeda ◽  
H. Takahashi ◽  
S. Shimizu ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Progression ◽  
Prothrombin Time ◽  
Univariate Analysis ◽  
Rank Test ◽  
Arterial Phase ◽  
Arterial Enhancement ◽  
Sorafenib Therapy ◽  
The Impact ◽  
Time To Tumor Progression

167 Background: In the diagnostic work-up of hepatocellular carcinoma (HCC), intratumoral enhancement in the arterial phase (IE) of dynamic computed tomography (CT) or magnetic resonance imaging (MRI) represents tumor viability. Although such IE has been known to disappear during the course of sorafenib therapy, the precise impact of decreased IE has not yet been elucidated. Therefore, we focused on the impact of decreased IE on the time-to-tumor progression (TTP) in HCC patients (pts) treated with sorafenib. Methods: The change in IEduring the course of sorafenib therapy was reviewed in 52advanced HCC patients treated between January 2004 and April 2010. decreased IE was defined as the disappearance of arterial enhancement to a level equal to or less than that of the surrounding cancer-free hepatic parenchyma on dynamic CT or MRI. Even if one of the HCC tumors in a patient showed decreased IE, that patient was regarded as showing decreased IE. The impact of the pretreatment variables, decreased IE, and adverse events on the TTP were evaluated by the log-rank test. The Cox proportional hazard model was used to determine the most significant variables related to TTP. Results: Of the 52 pts, 48 were males and 4 females, and the median age was 70.5 years. The Child-Pugh classification was A in 28 pts and B in 24 pts. HCV Ab positivity, HBs Ag positivity, and seronegativity for both were observed in 39 pts, 7 pts and 6 pts, respectively. Decreased IE was found in 23 patients. The median TTP was 114 days in all patients, 165 days in patients showing decreased IE, and 89 days in patients who did not show decreased IE. The median time to decreased IE was 41 days. In the univariate analysis, decreased IE, female, prothrombin time, and serum PIVKA II were identified as being significantly associated with the TTP. Multivariate analysis using the Cox proportional hazards model revealed decreased IE (p=0.04) and prothrombin time (p=0.04) to be independently associated with a favorable TTP. Conclusions: Decreased IE is correlated with a favorable time-to-tumor progression in HCC pts treated with sorafenib. No significant financial relationships to disclose.

scholarly journals Type III TGF-β Receptor Down-Regulation Promoted Tumor Progression via Complement Component C5a Induction in Hepatocellular Carcinoma

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1503
Author(s):  
Oscar Wai Ho Yeung ◽  
Xiang Qi ◽  
Li Pang ◽  
Hui Liu ◽  
Kevin Tak Pan Ng ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Tumor Progression ◽  
Tumor Stage ◽  
Complement Component ◽  
Soluble Form ◽  
Advanced Tumor Stage ◽  
Down Regulation ◽  
Type Iii ◽  
Advanced Tumor ◽  
Β Receptor

Background and Aims—Transforming growth factor-beta (TGF-β) signaling orchestrates tumorigenesis and one of the family members, TGF-β receptor type III (TGFβR3), are distinctively under-expressed in numerous malignancies. Currently, the clinical impact of TGFβR3 down-regulation and the underlying mechanism remains unclear in hepatocellular carcinoma (HCC). Here, we aimed to identify the tumor-promoting roles of decreased TGFβR3 expression in HCC progression. Materials and Methods—For clinical analysis, plasma and liver specimens were collected from 100 HCC patients who underwent curative resection for the quantification of TGFβR3 by q-PCR and ELISA. To study the tumor-promoting mechanism of TGFβR3 downregulation, HCC mouse models and TGFβR3 knockout cell lines were applied. Results—Significant downregulation of TGFβR3 and its soluble form (sTGFβR3) were found in HCC tissues and plasma compared to healthy individuals (p < 0.01). Patients with <9.4 ng/mL sTGFβR3 exhibited advanced tumor stage, higher recurrence rate and shorter disease-free survival (p < 0.05). The tumor-suppressive function of sTGFβR3 was further revealed in an orthotopic mouse HCC model, resulting in 2-fold tumor volume reduction. In TGFβR3 knockout hepatocyte and HCC cells, increased complement component C5a was observed and strongly correlated with shorter survival and advanced tumor stage (p < 0.01). Interestingly, C5a activated the tumor-promoting Th-17 response in tumor associated macrophages. Conclusion—TGFβR3 suppressed tumor progression, and decreased expression resulted in poor prognosis in HCC patients through upregulation of tumor-promoting complement C5a.

scholarly journals Hepatocellular carcinoma in HCV-infected patients awaiting liver transplantation: Genes involved in tumor progression

2004 ◽  
Vol 10 (5) ◽  
pp. 607-620 ◽  
Author(s):  
Valeria R. Mas ◽  
Daniel G. Maluf ◽  
Richard Stravitz ◽  
Catherine I. Dumur ◽  
Bradly Clark ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
Liver Transplantation ◽  
Tumor Progression
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