ly-2157299 and Liver-Neoplasms

Advanced hepatocellular carcinoma (HCC) carries a dismal prognosis and the current treatment is limited to sorafenib, an agent with modest benefit. Preclinical data have indicated that several immunologic mechanisms are at play to promote HCC development and growth while impairing effective antitumor immune surveillance. Several novel approaches geared toward manipulating the immune response to HCC have suggested a therapeutic benefit in early-stage clinical trials, indicating a real potential to augment tumor-specific immunity and improve outcomes in patients with this disease. In the current study, the authors reviewed the barriers to an effective immune response against HCC and contemporary clinical investigations that may be "primed" to alter the natural history of HCC.

Topics: Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; B7-H1 Antigen; Cancer Vaccines; Carcinoma, Hepatocellular; Clinical Trials as Topic; CTLA-4 Antigen; Cytokines; Hepatitis, Chronic; Humans; Immunotherapy; Interferons; Liver Neoplasms; Nivolumab; Oncolytic Virotherapy; Programmed Cell Death 1 Receptor; Pyrazoles; Quinolines; T-Lymphocytes; Tumor Escape

Hepatocellular carcinoma arises in patients as a consequence of long-standing preexisting liver illnesses, including viral hepatitis, alcohol abuse, or metabolic disease. In such preexisting liver diseases, TGF-β plays an important role in orchestrating a favorable microenvironment for tumor cell growth and promoting epithelial-mesenchymal transition (EMT). TGF-β signaling promotes hepatocellular carcinoma progression by two mechanisms: first, via an intrinsic activity as an autocrine or paracrine growth factor and, second, via an extrinsic activity by inducing microenvironment changes, including cancer-associated fibroblasts, T regulatory cells, and inflammatory mediators. Although there is an increasing understanding on how TGF-β signaling is associated with tumor progression in hepatocellular carcinoma, it is not clear whether TGF-β signaling is limited to a certain subgroup of patients with hepatocellular carcinoma or is a key driver of hepatocellular carcinoma during the entire tumorigenesis of hepatocellular carcinoma. Inhibitors of the TGF-β signaling have been shown to block hepatocellular carcinoma growth and progression by modulating EMT in different experimental models, leading to the clinical investigation of the TGF-β inhibitor LY2157299 monohydrate in hepatocellular carcinoma. Preliminary results from a phase II clinical trial have shown improved clinical outcome and also changes consistent with a reduction of EMT.

Topics: alpha-Fetoproteins; Carcinoma, Hepatocellular; Clinical Trials as Topic; Epithelial-Mesenchymal Transition; Humans; Liver Neoplasms; Pyrazoles; Quinolines; Signal Transduction; Transforming Growth Factor beta

Preclinical data suggest that vascular endothelial growth factor (VEGF) and transforming growth factor (TGF)-β signaling interact to stimulate angiogenesis and suppress antitumor immune responses. Thus, combined inhibition of both pathways may offer greater antitumor activity compared with VEGF-targeted antiangiogenic monotherapy against hepatocellular carcinoma (HCC).. This is a multicenter, open-label, phase 1b study of galunisertib, an inhibitor of TGF-β receptor 1, and ramucirumab, an anti-VEGF receptor 2 antibody, in patients with advanced HCC aiming to define the maximum tolerated dose (MTD). Secondary objectives included safety, pharmacokinetics (PK), antitumor efficacy, and plasma alpha-fetoprotein and TGF-β kinetics. Dose escalation employed a 3 + 3 design. Patients received galunisertib at 80 mg (cohort 1) or 150 mg (cohort 2) orally twice a day on days 1-14 of a 28-day cycle combined with ramucirumab 8 mg/kg intravenously every 2 weeks.. Eight patients were enrolled: three in cohort 1 and five in cohort 2 (two patients were unevaluable due to rapid disease progression and replaced). No dose-limiting toxicities were observed. Treatment-related adverse events (AEs) of any grade in ≥2 patients included nausea (25%) and vomiting (25%). There was one Grade 3 treatment-related AE, a cerebrovascular accident possibly related to ramucirumab. Galunisertib exposure was dose-proportional and not affected by ramucirumab. The RECIST version 1.1 objective response rate and disease control rate were 0% and 12.5%, respectively.. Combination therapy was safe and tolerable and displayed favorable PK. The MTD was established at galunisertib at 150 mg orally twice a day and ramucirumab 8 mg/kg intravenously every 2 weeks. The results do not support the preclinical hypothesis that blocking TGFβ signaling enhances efficacy of VEGF-targeted therapy; thus further clinical development was halted for the combination of galunisertib and ramucirumab.

Topics: Aged; Aged, 80 and over; alpha-Fetoproteins; Antibodies, Monoclonal, Humanized; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Female; Humans; Liver Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Nausea; Prospective Studies; Pyrazoles; Quinolines; Ramucirumab; Receptor, Transforming Growth Factor-beta Type I; Response Evaluation Criteria in Solid Tumors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Vomiting

Transforming growth factor beta (TGF-β) signalling is involved in the development of hepatocellular carcinoma (HCC). We followed changes in biomarkers during treatment of patients with HCC with the TGF-βRI/ALK5 inhibitor galunisertib.. This phase 2 study (NCT01246986) enrolled second-line patients with advanced HCC into one of two cohorts of baseline serum alpha-fetoprotein (AFP): Part A (AFP ≥1.5x ULN) or Part B (AFP <1.5x ULN). Baseline and postbaseline levels of AFP, TGF-β1, E-cadherin, selected miRNAs, and other plasma proteins were monitored.. The study enrolled 149 patients (Part A, 109; Part B, 40). Median OS was 7.3 months in Part A and 16.8 months in Part B. Baseline AFP, TGF-β1, E-cadherin, and an additional 16 plasma proteins (such as M-CSF, IL-6, ErbB3, ANG-2, neuropilin-1, MIP-3 alpha, KIM-1, uPA, IL-8, TIMP-1, ICAM-1, Apo A-1, CA-125, osteopontin, tetranectin, and IGFBP-1) were found to correlate with OS. In addition, a range of miRs were found to be associated with OS. In AFP responders (21% of patients in Part A with decrease of >20% from baseline) versus non-responders, median OS was 21.5 months versus 6.8 months (p = 0.0015). In TGF-β1 responders (51% of all patients) versus non-responders, median OS was 11.2 months versus 5.3 months (p = 0.0036).. Consistent with previous findings, both baseline levels and changes from baseline of circulating AFP and TGF-β1 function as prognostic indicators of survival. Future trials are needed to confirm and extend these results.

Topics: Adult; Aged; Aged, 80 and over; alpha-Fetoproteins; Antigens, CD; Biomarkers, Tumor; Cadherins; Carcinoma, Hepatocellular; Cohort Studies; Female; Humans; Liver Neoplasms; Male; MicroRNAs; Middle Aged; Prognosis; Pyrazoles; Quinolines; Receptor, Transforming Growth Factor-beta Type I; Survival Rate; Transforming Growth Factor beta1; Treatment Outcome

Background Galunisertib inhibits type I transforming growth factor-beta receptor serine/threonine kinase. The primary objective of this study was to evaluate the safety and tolerability of galunisertib in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma. Patients and methods This open-label, dose-escalation, multicenter, nonrandomized phase 1b study consisted of two dose levels of galunisertib, 160 or 300 mg/day, in combination with sorafenib 800 mg/day. Galunisertib 80 mg or 150 mg was administered orally twice daily for 14 days followed by 14 days of rest plus sorafenib 400 mg administered orally twice daily for 28 days. The dose-limiting toxicity evaluation was 28 days after the first dose. Safety measures, pharmacokinetics, and antitumor activity were assessed. Results Fourteen patients, 7 at each galunisertib dose, were enrolled and treated. Three dose-limiting toxicities were reported for 2 patients. The most common treatment-emergent adverse events (TEAEs) were hypophosphatemia (14 patients [100%]), palmar-plantar erythrodysesthesia syndrome (12 patients [85.7%]), and decreased platelet count (10 patients [71.4%]). The most common grade ≥ 3 TEAEs were hypophosphatemia (10 patients [71.4%]) and palmar-plantar erythrodysesthesia syndrome (7 patients [50.0%]). No grade 5 TEAEs were reported. The pharmacokinetic profile of galunisertib in combination with sorafenib was similar to that previously reported for galunisertib. Eleven patients had a best overall response of stable disease, and 1 patient achieved a partial response by hepatocellular carcinoma-specific modified RECIST. Conclusions These data are consistent with the known safety profile for galunisertib and sorafenib and confirm tolerability of the recommended dose of galunisertib (150 mg twice daily for 14 days) in combination with sorafenib in Japanese patients with unresectable hepatocellular carcinoma.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Hepatocellular; Female; Follow-Up Studies; Humans; Liver Neoplasms; Male; Maximum Tolerated Dose; Middle Aged; Prognosis; Pyrazoles; Quinolines; Receptor, Transforming Growth Factor-beta Type I; Sorafenib; Tissue Distribution

We assessed the activity of galunisertib, a small molecule inhibitor of the transforming growth factor beta (TGF-β1) receptor I, in second-line patients with hepatocellular carcinoma (HCC) in two cohorts of baseline serum alpha fetoprotein (AFP).. Patients with advanced HCC who progressed on or were ineligible to receive sorafenib, Child-Pugh A/B7 and ECOG PS ≤1 were enrolled into Part A (AFP ≥ 1.5× ULN) or Part B (AFP < 1.5× ULN). Patients were treated with 80 or 150 mg galunisertib BID for 14 days per 28-day cycle. Endpoints were time-to-progression (TTP) and changes in circulating AFP and TGF-β1 levels, as well as safety, pharmacokinetics, progression-free survival and overall survival (OS).. Patients (n = 149) were enrolled with median age 65 years. Median TTP was 2.7 months (95% CI: 1.5-2.9) in Part A (n = 109) and 4.2 months (95% CI: 1.7-5.5) in Part B (n = 40). Median OS was 7.3 months (95% CI: 4.9-10.5) in Part A and 16.8 months (95% CI: 10.5-24.4) in Part B. OS was longer in AFP responders (>20% decrease from baseline, Part A) compared to non-responders (21.5 months vs 6.8 months). OS was longer in TGF-β1 responders (>20% decrease from baseline, all patients) compared to non-responders. The most common Grade 3/4 treatment-related adverse events were neutropenia (n = 4) and fatigue, anaemia, increased bilirubin, hypoalbuminemia and embolism (each, n = 2).. Galunisertib treatment had a manageable safety profile in patients with HCC. Lower baseline AFP and a response in AFP or TGF-β1 levels (vs no response) correlated with longer survival.. NCT01246986 at ClinicalTrials.gov.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Hepatocellular; Female; Humans; Liver Neoplasms; Male; Middle Aged; Pyrazoles; Quinolines; Receptor, Transforming Growth Factor-beta Type I

Inhibition of tumor growth factor-β (TGF-β) receptor type I potentiated the activity of sorafenib in preclinical models of hepatocellular carcinoma (HCC). Galunisertib is a small-molecule selective inhibitor of TGF-β1 receptor type I, which demonstrated activity in a phase 2 trial as second-line HCC treatment.. The combination of galunisertib and sorafenib (400 mg BID) was tested in patients with advanced HCC and Child-Pugh A liver function without prior systemic therapy. Galunisertib dose was administered 80 or 150 mg b.i.d. orally for 14 days every 28 days in safety lead-in cohorts; in the expansion cohort, all patients received galunisertib 150 mg b.i.d. Objectives included time-to-tumor progression, changes in circulating alpha fetoprotein and TGF-β1, safety, overall survival (OS), response rate, and pharmacokinetics (PK).. Patients (n = 47) were enrolled from 5 non-Asian countries; 3 and 44 patients received the 80 mg and 150 mg b.i.d. doses of galunisertib, respectively. The pharmacokinetics and safety profiles were consistent with monotherapy of each drug. For the 150 mg b.i.d. galunisertib cohort, the median time-to-tumor progression was 4.1 months; the median OS was 18.8 months. A partial response was seen in 2 patients, stable disease in 21, and progressive disease in 13. TGF-β1 responders (decrease of >20% from baseline) vs nonresponders had longer OS (22.8 vs 12.0 months, P = 0.038).. The combination of galunisertib and sorafenib showed acceptable safety and a prolonged OS outcome.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; alpha-Fetoproteins; Carcinoma, Hepatocellular; Case-Control Studies; Disease Progression; Drug Therapy, Combination; Female; Humans; Liver Neoplasms; Male; Middle Aged; Protein Kinase Inhibitors; Pyrazoles; Quinolines; Receptors, Transforming Growth Factor beta; Safety; Sorafenib; Transforming Growth Factor beta1; Treatment Outcome

TGFβ is a pleiotropic cytokine with immunosuppressive activity. In preclinical models, blockade of TGFβ enhances the activity of radiation and invokes T-cell antitumor immunity. Here, we combined galunisertib, an oral TGFβ inhibitor, with stereotactic body radiotherapy (SBRT) in patients with advanced hepatocellular carcinoma (HCC) and assessed safety, efficacy, and immunologic correlatives. Patients (

Topics: Aged; Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Male; Middle Aged; Pilot Projects; Pyrazoles; Quinolines; Radiosurgery

Oncolytic reovirus, which is a non-enveloped virus possessing a 10-segmented double-stranded RNA genome, has been anticipated as a novel class of antitumor agent. Hepatocellular carcinoma (HCC) is considered to be a target suitable for reovirus-mediated virotherapy. Transforming growth factor (TGF)-β plays an important role in the pathogenesis of HCC. TGF-β-signaling inhibitors have proceeded to clinical trials as potential antitumor agents for HCC. On the other hand, TGF-β is involved in induction of expression of cathepsins B and L, which are important for reovirus infection. It remains to be examined whether TGF-β signaling inhibitors affect reovirus-mediated lysis of HCC cells. The aim of this study was to evaluate the effects of TGF-β-signaling inhibitors on tumor cell lysis efficiency of reovirus in human HCC cells.. Reovirus was added to four types of human HCC cell lines pretreated with one of three TGF-β type I receptor inhibitors: SB431542, A-83-01, or galunisertib (LY2157299). Cell viability, virus genome copy numbers, and virus protein expression were evaluated following reovirus infection.. SB431542 significantly inhibited reovirus-mediated killing of human HCC cell lines, while A-83-01 and galunisertib did not inhibit.. These data indicate that SB431542 inhibited reovirus-mediated lysis of human HCC cells in a TGF-β signaling-independent manner.

Topics: Benzamides; Carcinoma, Hepatocellular; Cell Survival; Dioxoles; Epoxy Compounds; Humans; Liver Neoplasms; Orthoreovirus, Mammalian; Pyrazoles; Quinolines; RNA, Double-Stranded; Signal Transduction; Transforming Growth Factor beta1; Tyrosine

Topics: Antibodies, Monoclonal, Humanized; Antineoplastic Agents, Immunological; B7-H1 Antigen; Carcinoma, Hepatocellular; Gene Expression Regulation, Neoplastic; Genome, Human; Humans; Immunotherapy, Adoptive; Liver Neoplasms; Phenylurea Compounds; Programmed Cell Death 1 Receptor; Pyrazoles; Quinolines; Sunitinib; T-Lymphocytes, Regulatory; Transforming Growth Factor beta; Tumor-Associated Macrophages

Topics: ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily G, Member 2; Carcinoma, Hepatocellular; Cell Proliferation; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic; Hep G2 Cells; Humans; Inactivation, Metabolic; Liver Neoplasms; MAP Kinase Signaling System; Multidrug Resistance-Associated Protein 2; Multidrug Resistance-Associated Proteins; Pregnane X Receptor; Proto-Oncogene Protein c-ets-1; Pyrazoles; Quinolines; Transforming Growth Factor beta

Topics: Carcinoma, Hepatocellular; Humans; Liver Neoplasms; Pyrazoles; Quinolines; Receptor, Transforming Growth Factor-beta Type I

Cancer stem cells (CSCs) niche in the tumor microenvironment is responsible for cancer recurrence and therapy failure. To better understand its molecular and biological involvement in hepatocellular carcinoma (HCC) progression, one can design more effective therapies and tailored then to individual patients. While sorafenib is currently the only approved drug for first-line treatment of advanced stage HCC, its role in modulating the CSC niche is estimated to be small. By contrast, transforming growth factor (TGF)-β pathway seems to influence the CSC and thus may impact hallmarks of HCC, such as liver fibrosis, cirrhosis, and tumor progression. Therefore, blocking this pathway may offer an appealing and druggable target. In our study, we have used galunisertib (LY2157299), a selective ATP-mimetic inhibitor of TGF-β receptor I (TGFβI/ALK5) activation, currently under clinical investigation in HCC patients. Because the drug resistance is mainly mediated by CSCs, we tested the effects of galunisertib on stemness phenotype in HCC cells to determine whether TGF-β signaling modulates CSC niche and drug resistance. Galunisertib modulated the expression of stemness-related genes only in the invasive (HLE and HLF) HCC cells inducing a decreased expression of CD44 and THY1. Furthermore, galunisertib also reduced the stemness-related functions of invasive HCC cells decreasing the formation of colonies, liver spheroids and invasive growth ability. Interestingly, CD44 loss of function mimicked the galunisertib effects on HCC stemness-related functions. Galunisertib treatment also reduced the expression of stemness-related genes in ex vivo human HCC specimens. Our observations are the first evidence that galunisertib effectiveness overcomes stemness-derived aggressiveness via decreased expression CD44 and THY1.

Topics: Blotting, Western; Carcinoma, Hepatocellular; Cell Line, Tumor; Flow Cytometry; Hep G2 Cells; Humans; Hyaluronan Receptors; In Vitro Techniques; Liver Neoplasms; Neoplastic Stem Cells; Pyrazoles; Quinolines; Receptors, Transforming Growth Factor beta; Signal Transduction; Transforming Growth Factor beta1

Transforming growth factor β (TGFβ) is a multifunctional cytokine which is importantly implicated in hepatocarcinogenesis. The current study provides novel evidence that TGFβ upregulates the expression of multiple receptor tyrosine kinases (RTKs), including IGF1R, EGFR, PDGFβR, and FGFR1 in human hepatocellular carcinoma (HCC) cells. This, in turn, sensitized HCC cells to individual cognate RTK ligands, leading to cell survival. Our data showed that the TGFβ-mediated increase in growth factor sensitivity led to evasion of apoptosis induced by the mutikinase inhibitor, sorafenib. Conversely, we observed that inhibition of the TGFβ signaling pathway by LY2157299, a TGFβRI kinase inhibitor, enhanced sorafenib-induced apoptosis, in vitro. Our findings disclose an important interplay between TGFβ and RTK signaling pathways, which is critical for hepatocellular cancer cell survival and resistance to therapy. © 2016 Wiley Periodicals, Inc.

Topics: Antineoplastic Agents; Apoptosis; Carcinoma, Hepatocellular; Cell Line, Tumor; Drug Resistance, Neoplasm; Humans; Liver; Liver Neoplasms; Niacinamide; Phenylurea Compounds; Pyrazoles; Quinolines; Receptor Protein-Tyrosine Kinases; Signal Transduction; Sorafenib; Transforming Growth Factor beta

Transforming growth factor-beta (TGF-β) signaling has gained extensive interest in hepatocellular carcinoma (HCC). The small molecule kinase inhibitor galunisertib, targeting the TGF-β receptor I (TGF-βRI), blocks HCC progression in preclinical models and shows promising effects in ongoing clinical trials. As the drug is not similarly effective in all patients, this study was aimed at identifying new companion diagnostics biomarkers for patient stratification. Next-generation sequencing-based massive analysis of cDNA ends was used to investigate the transcriptome of an invasive HCC cell line responses to TGF-β1 and galunisertib. These identified mRNA were validated in 78 frozen HCC samples and in 26 ex-vivo HCC tissues treated in culture with galunisertib. Respective protein levels in patients blood were measured by enzyme-linked immunosorbent assay. SKIL, PMEPA1 ANGPTL4, SNAI1, Il11 and c4orf26 were strongly upregulated by TGF-β1 and downregulated by galunisertib in different HCC cell lines. In the 78 HCC samples, only SKIL and PMEPA1 (P<0.001) were correlated with endogenous TGF-β1. In ex-vivo samples, SKIL and PMEPA1 were strongly downregulated (P<0.001), and correlated (P<0.001) with endogenous TGF-β1. SKIL and PMEPA1 mRNA expression in tumor tissues was significantly increased compared with controls and not correlated with protein levels in the blood of paired HCC patients. SKIL and PMEPA1 mRNA levels were positively correlated with TGF-β1 mRNA concentrations in HCC tissues and strongly downregulated by galunisertib. The target genes identified here may serve as biomarkers for the stratification of HCC patients undergoing treatment with galunisertib.

Topics: Biomarkers, Tumor; Carcinoma, Hepatocellular; Cell Line, Tumor; Down-Regulation; Gene Expression Profiling; Hep G2 Cells; Humans; Liver Neoplasms; Membrane Proteins; Proto-Oncogene Proteins; Pyrazoles; Quinolines; Receptors, Transforming Growth Factor beta; RNA, Messenger; Signal Transduction; Transcriptome; Transforming Growth Factor beta1; Up-Regulation

Galunisertib (LY2157299) is a selective ATP-mimetic inhibitor of TGF-β receptor (TβR)-I activation currently under clinical investigation in hepatocellular carcinoma (HCC) patients. Our study explored the effects of galunisertib in vitro in HCC cell lines and ex vivo on patient samples. Galunisertib was evaluated in HepG2, Hep3B, Huh7, JHH6 and SK-HEP1 cells as well as in SK-HEP1-derived cells tolerant to sorafenib (SK-Sora) and sunitinib (SK-Suni). Exogenous stimulation of all HCC cell lines with TGF-β yielded downstream activation of p-Smad2 and p-Smad3 that was potently inhibited with galunisertib treatment at micromolar concentrations. Despite limited antiproliferative effects, galunisertib yielded potent anti-invasive properties. Tumor slices from 13 patients with HCC surgically resected were exposed ex vivo to 1 µM and 10 µM galunisertib, 5 µM sorafenib or a combination of both drugs for 48 hours. Galunisertib but not sorafenib decreased p-Smad2/3 downstream TGF-β signaling. Immunohistochemistry analysis of galunisertib and sorafenib-exposed samples showed a significant decrease of the proliferative marker Ki67 and increase of the apoptotic marker caspase-3. In combination, galunisertib potentiated the effect of sorafenib efficiently by inhibiting proliferation and increasing apoptosis. Our data suggest that galunisertib may be active in patients with HCC and could potentiate the effects of sorafenib.

Topics: Adult; Aged; Carcinoma, Hepatocellular; Caspase 3; Cell Line, Tumor; Cell Proliferation; Female; Hep G2 Cells; Humans; Immunohistochemistry; Indoles; Ki-67 Antigen; Liver Neoplasms; Male; Middle Aged; Neoplasm Invasiveness; Niacinamide; Phenylurea Compounds; Pyrazoles; Pyrroles; Quinolines; Signal Transduction; Sorafenib; Sunitinib; Transforming Growth Factor beta1

We investigated blocking the TGF-β signaling pathway in HCC using two small molecule inhibitors (LY2157299, LY2109761) and a neutralizing humanized antibody (D10) against TGF-βRII. LY2157299 and LY2109761 inhibited HCC cell migration on Laminin-5, Fibronectin, Vitronectin, Fibrinogen and Collagen-I and de novo phosphorylation of pSMAD2. LY2157299 inhibited HCC migration and cell growth independently of the expression levels of TGF-βRII. In contrast to LY2157299, D10 showed a reduction in pSMAD2 only after a short exposure. This study supports the use of LY2157299 in clinical trials, and presents new insights into TGF-β receptor cycling in cancer cells.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Hepatocellular; Connective Tissue Growth Factor; Female; Hep G2 Cells; Homeodomain Proteins; Humans; Liver Neoplasms; Male; Middle Aged; Protein Serine-Threonine Kinases; Pyrazoles; Pyrroles; Quinolines; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; Signal Transduction; Smad2 Protein; Transcription Factors; Transforming Growth Factor beta; Vascular Endothelial Growth Factor A