Multi Kinase Research Articles

Discovery of DS79182026: A potent orally active hepcidin production inhibitor

Hepcidin has emerged as the central regulatory molecule of systemic iron homeostasis. Inhibition of hepcidin could be a strategy favorable to treating anemia of chronic disease (ACD). We report herein the synthesis and structure-activity relationships (SARs) of a series of benzisoxazole compounds as orally active hepcidin production inhibitors. The optimization study of multi kinase inhibitor 1 led to a potent and bioavailable hepcidin production inhibitor 38 (DS79182026), which showed serum hepcidin lowering effects in a mouse IL-6 induced acute inflammatory model.

Regorafenib inhibited gastric cancer cells growth and invasion via CXCR4 activated Wnt pathway.

AimRegorafenib is an oral small-molecule multi kinase inhibitor. Recently, several clinical trials have revealed that regorafenib has an anti-tumor activity in gastric cancer. However, only part of patients benefit from regorafenib, and the mechanisms of regorafenib’s anti-tumor effect need further demonstrating. In this study, we would assess the potential anti-tumor effects and the underlying mechanisms of regorafenib in gastric cancer cells, and explore novel biomarkers for patients selecting of regorafenib.MethodsThe anti-tumor effects of regorafenib on gastric cancer cells were analyzed via cell proliferation and invasion. The underlying mechanisms were demonstrated using molecular biology techniques.ResultsWe found that regorafenib inhibited cell proliferation and invasion at the concentration of 20μmol/L and in a dose dependent manner. The anti-tumor effects of regorafenib related to the decreased expression of CXCR4, and elevated expression and activation of CXCR4 could reverse the inhibition effect of regorafenib on gastric cancer cells. Further studies revealed that regorafenib reduced the transcriptional activity of Wnt/β-Catenin pathway and led to decreased expression of Wnt pathway target genes, while overexpression and activation of CXCR4 could attenuate the inhibition effect of regorafenib on Wnt/β-Catenin pathway.ConclusionsOur findings demonstrated that regorafenib effectively inhibited cell proliferation and invasion of gastric cancer cells via decreasing the expression of CXCR4 and further reducing the transcriptional activity of Wnt/β-Catenin pathway.

Management of treatment-related toxicity caused by multi kinase inhibitors administered due to advanced thyroid carcinoma

Management of treatment-related toxicity caused by multi kinase inhibitors administered due to advanced thyroid carcinoma

Cooperation between an endocrine nurse, psychologist and physician and their mediating role in the care of depression in patients treated with multi kinase inhibitors due thyroid cancer

Cooperation between an endocrine nurse, psychologist and physician and their mediating role in the care of depression in patients treated with multi kinase inhibitors due thyroid cancer

MP73-05 ACTIVATION OF SERINE BIOSYNTHESIS PATHWAY IN HIF2? ANTAGONIST-RESISTANT RENAL CELL CARCINOMA CELLS AFTER ACQUIRING SUNITINIB RESISTANCE: RESULTS FROM THE GENOME EDITING TECHNOLOGY

You have accessJournal of UrologyKidney Cancer: Basic Research & Pathophysiology III1 Apr 2017MP73-05 ACTIVATION OF SERINE BIOSYNTHESIS PATHWAY IN HIF2? ANTAGONIST-RESISTANT RENAL CELL CARCINOMA CELLS AFTER ACQUIRING SUNITINIB RESISTANCE: RESULTS FROM THE GENOME EDITING TECHNOLOGY Hideki Enokida, Hirofumi Yoshino, Kazutaka Miyamoto, Masaya Yonemori, Satoru Sugita, Takashi Sakaguchi, and Masayuki Nakagawa Hideki EnokidaHideki Enokida More articles by this author , Hirofumi YoshinoHirofumi Yoshino More articles by this author , Kazutaka MiyamotoKazutaka Miyamoto More articles by this author , Masaya YonemoriMasaya Yonemori More articles by this author , Satoru SugitaSatoru Sugita More articles by this author , Takashi SakaguchiTakashi Sakaguchi More articles by this author , and Masayuki NakagawaMasayuki Nakagawa More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2017.02.3350AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES ontinuous activation of hypoxia-inducible factor (HIF) is important for renal cell carcinoma (RCC) progression as well as resistance acquisition against mTOR and VEGFR inhibitors. Recently a HIF2α antagonist (PT2385) has been developed, and is currently being investigated in a phase I clinical trial for advanced or metastatic clear cell RCC (ccRCC) patients who had prior tyrosine kinase inhibitors. However, resistant mechanisms against the HIF2α antagonist seems to be a next problem in the near future. The aim of this study was to find activated signals involved in the HIF2α antagonist-resistance after acquiring sunitinib resistance. METHODS First, we established sunitinib resistant 786-o (SU-R-786-o) cells in vivo by oral gavage treatment. Instead of the HIF2α antagonist administration, we completely knocked out the HIF2α gene expression in SU-R-786-o cells by using a recent genome editing technology, CRISPR/Cas9 system, with two different single guide RNAs against HIF2α. We identified their characteristics in cell proliferation assay and western blot. These cells were also analyzed in proteomics and RNA sequence analyses to elucidate their activated signals. RESULTS By using CRISPR/Cas9 system, we succeeded in establishing HIF2α knockout sunitinib resistant 786-o (HIF2α-KO-SU-R-786-o) cells. Cell morphology was changed from spindle to round shape in HIF2α-KO-SU-R-786-o cells. In addition, cell proliferation in HIF2α-KO-SU-R-786-o cells became significantly slower than in the parental cells as well as SU-R-786-o cells (P < 0.01). After recovering cell proliferation in HIF2α-KO-SU-R-786-o cells, proteomics and RNA sequence revealed that CXCR4 expression was dramatically up-regulated in SU-R-786-o cells compared to the parental cells, however, it was decreased in HIF2α-KO-SU-R-786-o cells compared to SU-R-786-o cells. Another surprise was that serine biosynthesis pathway was accelerated in HIF2α-KO-SU-R-786-o cells compared to SU-R-786-o cells. CONCLUSIONS Based on the proteomics and RNA sequence analyses, we found that CXCR4 upregulation or serine biosynthesis might be critical for acquiring resistance against multi kinase inhibitors or HIF2α antagonist. Even though both drugs target angiogenesis pathway, the activated signals were altered in the different therapeutic stage by the different drugs administration. The inhibitions of serine biosynthesis pathways might be potential targeted therapy for advanced or metastatic ccRCC which shows resistance to HIF2α agonist after acquiring resistance to multi kinase inhibitors. © 2017FiguresReferencesRelatedDetails Volume 197Issue 4SApril 2017Page: e965 Advertisement Copyright & Permissions© 2017MetricsAuthor Information Hideki Enokida More articles by this author Hirofumi Yoshino More articles by this author Kazutaka Miyamoto More articles by this author Masaya Yonemori More articles by this author Satoru Sugita More articles by this author Takashi Sakaguchi More articles by this author Masayuki Nakagawa More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...

Multikinase inhibitors sorafenib and sunitinib as radiosensitizers in head and neck cancer cell lines.

Radioresistance is a common feature of head and neck squamous cell carcinoma (HNSCC). We previously showed that the irradiation- activated vascular endothelial growth factor (VEGF)-extracellular signal-regulated kinase (ERK)-axis is fundamental for the survival of resistant tumors. In this study, we examined if treatment with potent multikinase (MK) inhibitors, sorafenib and sunitinib, could radiosensitize tumor cells. Cultured HNSCC cell lines were treated with inhibitors and subsequently irradiated. Radiosensitizing effects were functionally assessed by annexin-V apoptosis and clonogenic assays and confirmed by Western blot. Additionally, we surveyed human HNSCC tissue microarrays (TMAs) for activated ERK expression. Based on combination indexes, we found that combining irradiation with both inhibitors exerted strong and supra-additive antitumor effects on clonogenic survival. Kinase inhibition enhanced irradiation-induced apoptotic rates and inhibited postradiogenic phospho-ERK-expression. Patients with recurrent HNSCC displayed significantly lower extracellular signal-regulated kinase phosphorylation (pERK) levels than relapse-free patients. We propose further evaluation of sorafenib and sunitinib as potential radiosensitizing agents in HNSCC treatment. © 2017 Wiley Periodicals, Inc. Head Neck 39: 623-632, 2017.

Interaction between regorafenib and warfarin therapy.

651 Background: Regorafenib is an oral multi kinase inhibitor with clinical activity in colorectal cancer, gastrointestinal stromal tumors and hepatocellular cancer. Drug- drug interactions are commonly encountered in clinical practice and warfarin continues to be the most commonly prescribed anticoagulant among cancer patients in the clinic. The interaction of regorafenib with warfarin has not been studied. Methods: Patients at a single institution being prescribed regorafenib were identified and charts reviewed for concurrent warfarin therapy. Baseline characteristics, indications for regorafenib and warfarin therapy was determined. Patients were followed up to the first 8 weeks of combination therapy. Results: We identified 6 patients on concurrent regorafenib and warfarin. All patients had refractory colon cancer. Median age was 74, 4 were male and 5 white. Indication for warfarin was venous thromboembolism in 5 and atrial fibrillation in 1. Baseline INR ranged from 1.1 to 2.4. An increase in INR was seen in all six patients (peak INR range 4.5 to &gt; 12) which improved with dose modification. Time to peak INR was less than 6 weeks (INR trends in all patients shown in figure 1). There were no bleeding complications noted in any patient. Conclusions: We report a clinically significant interaction between warfarin and regorafenib with patients demonstrating an increase in INR. Patients who are anticoagulated with warfarin and start regorafenib should be closely monitored and upfront warfarin dose reduction should be considered. Further drug-drug interaction studies are needed to determine the exact mechanism of drug-drug interaction between these medications.

SC11.03 ROS1 as a Therapeutic Target in Advanced NSCLC

SC11.03 ROS1 as a Therapeutic Target in Advanced NSCLC

P2.04-019 A Peripheral Immune Signature Associated with Clinical Activity of Sunitinib in Thymic Carcinoma: Topic: Thymic Malignancies Clinical and Translational

We have previously reported an objective response rate of 26% and disease stabilization in 65% of patients with advanced thymic carcinoma (TC) treated with the multi kinase inhibitor sunitinib after failure of platinum-based chemotherapy. The current study investigates the impact of sunitinib on systemic immunity in patients with thymic epithelial tumors with an aim to discover blood-based, predictive immune biomarkers. Patients with thymoma and TC received sunitinib at a dose of 50 mg once daily in 6-week cycles consisting of 4 weeks of treatment followed by 2 weeks without treatment. Results from 15 patients with TC are reported here. Blood samples were collected before initiation of sunitinib therapy (Cycle 1 day 1; C1D1), and prior to treatment on day 1 of cycles 2 and 3 (C2D1; C3D1). Multiparameter flow cytometry was used to study T-cell subsets with immune checkpoint expression, four phenotypes of myeloid-derived suppressor cells (MDSCs) with CD40, and CD14+ monocytes with HLA-DR expression. Expression of 730 immune-related genes in peripheral blood was analyzed by NanoString technology. Differences in paired markers or changes in markers between two time points was evaluated by the Wilcoxon signed rank test. The Kaplan-Meier method was used to obtain estimates of progression-free survival (PFS) and overall survival (OS). Immunosuppressive Tim-3-positive Tregs declined after 2 cycles of sunitinib (p=0.024). A decrease in granulocytic MDSCs (p=0.012), lineage negative (CD3-CD19-CD56-) MDSCs (p=0.013), and immature MDSCs (p=0.01) but not monocytic MDSCs was observed after 1 cycle of sunitinib. TC patients with no objective response to sunitinib had a higher baseline immature MDSC level than responders (p=0.0044). Greater than median declines in granulocytic MDSC CD40 (C2D1 p=0.027, C3D1 p=0.0046) and lineage-MDSC CD40 (C3D1, p=0.0046) after sunitinib therapy was associated with improved PFS. Similarly, a greater than median decline in CD14+HLA-DRlo/neg monocyte levels on C2D1 was associated with longer PFS (p=0.020). Among the immune genes examined, higher baseline FEZ1 expression was associated with improved PFS and OS. Our findings suggest significant interplay between sunitinib and systemic immunity impacts therapeutic outcome in TC. Monitoring CD40 expression on specific MDSC phenotypes and FEZ1 gene expression may predict a survival benefit after treatment with sunitinib. These results, if validated in larger studies, can serve as potential blood-based predictive biomarkers in TC patients treated with sunitinib.

The noni anthraquinone damnacanthal is a multi-kinase inhibitor with potent anti-angiogenic effects

The natural bioactive compound damnacanthal inhibits several tyrosine kinases. Herein, we show that -in fact- damancanthal is a multi kinase inhibitor. A docking and molecular dynamics simulation approach allows getting further insight on the inhibitory effect of damnacanthal on three different kinases: vascular endothelial growth factor receptor-2, c-Met and focal adhesion kinase. Several of the kinases targeted and inhibited by damnacanthal are involved in angiogenesis. Ex vivo and in vivo experiments clearly demonstrate that, indeed, damnacanthal is a very potent inhibitor of angiogenesis. A number of in vitro assays contribute to determine the specific effects of damnacanthal on each of the steps of the angiogenic process, including inhibition of tubulogenesis, endothelial cell proliferation, survival, migration and production of extracellular matrix remodeling enzyme. Taken altogether, these results suggest that damancanthal could have potential interest for the treatment of cancer and other angiogenesis-dependent diseases.

Efficacy of lenvatinib in treating thyroid cancer

ABSTRACTIntroduction: Radioiodine [RAI]-resistant advanced and progressive differentiated thyroid cancer [DTC], although rare, constitutes a real challenge as its prognosis is poor and available therapeutic options, until now, have been limited. Discovery of a crucial role of distinct tyrosine kinases in DTC pathogenesis opened up new options in systemic treatment. Lenvatinib is an oral potent multi kinase inhibitor [MKI] of different growth factor receptors including VEGFR1/Flt-1, VEGFR2/KDR, VEGFR3, FGFR1,2,3,4, PDGFR-β as well as RET and KIT signaling networks. Its activity against RAI-refractory DTC was demonstrated in clinical studies fulfilling evidence-based medicine [EBM] criteria. The drug showed acceptable tolerance and manageable toxicity.Areas covered: published results of phase II and III studies and other reports evaluated the efficacy and safety of lenvatinib in DTC and in medullary thyroid carcinoma.Expert opinion: Currently there are two different MKIs, lenvatinib and sorafenib, which have demonstrated effectiveness against RAI-refractory DTC. However, to date, the question of which drug should be chosen for first line treatment remains open. The other question: when to start the treatment seems to be no less important. Whether disease progression, even by RECIST, is enough to initiate a therapy or tumor burden also plays an important role? EBM study, to resolve these issues, is our task for the nearest future.

Abstract LB-C17: A phase I study of everolimus (mTOR inhibitor) in combination with vandetanib (multikinase inhibitor of VEGFR, EGFR, and RET) in advanced solid tumors including molecularly matched aberrations

Abstract Background: RET gene aberrations including fusions have been identified across several types of solid malignancies, including lung adenocarcinomas, thyroid, colorectal and invasive breast cancers. Preclinical models has shown that the combination of vandetanib (VAN), a multi tyrosine kinase inhibitor of VEGFR2/EGFR and RET pathways) and everolimus (EV), an mTOR pathway inhibitor, overcomes intrinsic and /or acquired tumor resistance to either agent alone, suggesting a rationale for investigating this combination in cancer patients, including those harboring aberrations in the drug targets. Methods: We designed a dose escalation and expansion trial with “3+3” design to determine the safety, maximum tolerated dose (MTD), recommended Phase II dose (RP2D), dose-limiting toxicities (DLTs) and activity of the combination. During the escalation phase, the study drugs (VAN, EV) were given at the following doses, respectively: level 0 (100 mg, 2.5 mg), level 1 (200mg, 2.5mg), level 2 (200mg, 5mg), level 3 (300 mg, 5mg), and level 4 (300mg, 10mg). Both study drugs are given continuously on a 28 day schedule. Tumor responses are assessed using RECIST v1.1. Tumor molecular aberrations were detected by Next Generation Sequencing (NSG) and/or Fluorescence In Situ Hybridization (FISH). Results: To date, 72 adult patients have been treated. Median age was 56 years (range 18-82 years) and 38 patients (53%) were male. The most common diagnoses were sarcoma (n = 15); renal cell carcinoma (n = 11); thyroid cancer (n = 10; n = 3 medullary) lung cancer (n = 10). Thirty patients (41%) had 3 or more sites of metastases. Nine patients were treated at dose level 0 (VAN 100 mg daily + EV 2.5 mg daily), five at dose level 1 (VAN 200 mg daily + EV 2.5 mg daily), and 6 patients at dose level 4 (highest dose VAN 300 mg daily + EV 10 mg daily). The most common adverse events observed in patients across different dose levels included G1 rash (n = 10), G1-G3 diarrhea (n = 21); G1-G4 thrombocytopenia (n = 9); G1-G2 hypertriglyceridemia/hypercholesterolemia (n = 8); G1-G2 hypertension (n = 6), G1-G2 QTc prolongation (n = 4); G1-G transaminitis (n = 4). Dose escalation has been completed and the expansion phase is currently ongoing in patients with advanced malignancies harboring RET, or P13K, PIK3R1, TSC1/2 and AKT genomic aberrations. The best responses were PR (n = 7), and SD (n = 33). Ten patients with reported SD (30.3%) experienced durable responses (&amp;gt; 6 months). One RET M918T mutant medullary thyroid cancer patient, who developed acquired resistance to VAN, achieved a 25% reduction on this combination. Three NSCLC patients with RET fusions (100%) responded with one reaching 48% decrease per RECIST. In addition there was evidence of blood-brain barrier penetration in 2 patients with RET fusion patients who had brain metastases. Conclusions: The combination of VAN and EV was reasonably well tolerated at the highest doses of each of the drugs. Evidence of response was noted in heavily pre-treated patients with refractory solid tumors and targetable genomic aberrations specifically RET. The combination has CNS penetration in RET fusion NSCLC. Citation Format: Tina Cascone, Kenneth R. Hess, Sarina Piha-Paul, David S. Hong, Michael Roxas, Ishwaria M. Subbiah, Siquing Fu, Aung Naing, Filip Janku, Daniel Karp, Steven I. Sherman, Funda Meric-Bernstam, John V. Heymach, Vivek Subbiah. A phase I study of everolimus (mTOR inhibitor) in combination with vandetanib (multikinase inhibitor of VEGFR, EGFR, and RET) in advanced solid tumors including molecularly matched aberrations. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C17.

Involvement of Notch-1 in Resistance to Regorafenib in Colon Cancer Cells.

Regorafenib, an oral small-molecule multi kinase inhibitor, is able to block Vascular Endothelial Growth Factor Receptors (VEGFR-1, 2, and 3), Platelet-Derived Growth Factor Receptors (PDGF), Fibroblast Growth Factor (FGF) receptor 1, Raf, TIE-2, and the kinases KIT, RET, and BRAF. Different studies have displayed its antitumor activity in several cancer models (both in vitro and in vivo), particularly in colorectal and gastrointestinal stromal cancers. The mechanism of resistance to regorafenib is largely unknown. In our investigation, we have generated regorafenib-resistant SW480 cells (Reg-R-SW480 cells) by culturing such cells with increasing concentration of regorafenib. Examination of intracellular signaling found that Akt signaling was activated in Reg-R-SW480 cells but not in wild-type SW480 cells, after regorafenib treatment as measured by Western Blot. The Notch pathway is a fundamental signaling system in the development and homeostasis of tissues since it regulates different cellular process such as proliferation, differentiation, and apoptosis and it can be a potential driver of resistance to a wide array of targeted therapies. In this study, we found that Notch-1 was significantly up-regulated in resistant tumor cells as well as HES1 and HEY. Additionally, inhibition of Notch-1 in resistant cells partially restored sensitivity to regorafenib treatment in vitro. Collectively, these data suggest a key role of Notch-1 in mediating the resistant effects of regorafenib in colorectal cancer cells, and also provide a rationale to improve the therapeutic efficacy of regorafenib.

Critical appraisal of the use of regorafenib in the management of colorectal cancer

The lack of valid clinical management options for patients affected by metastatic colorectal cancer, which has progressed after all approved standard treatments, has lead to research into new active molecules. Regorafenib is an oral small-molecule multi kinase inhibitor, binding to several intracellular kinases, with powerful inhibitory activity against vascular endothelial growth factor receptors (VEGFR-1,VEGFR-2, and VEGFR-3), platelet-derived growth factor receptor, fibroblast growth factor receptor 1, Raf, TIE-2, and the kinases KIT, RET, and BRAF. The antitumor activity of regorafenib has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in several cancer models, particularly colorectal cancer and gastrointestinal stromal tumors. The most frequent adverse events of grade 3 or higher related to regorafenib were hand-foot skin reaction, fatigue, diarrhea, hypertension, and rash or desquamation. Only a few Phase I–II trials, and most recently a Phase III trial in pretreated colorectal cancer, have been carried out to date. Several ongoing trials are testing the efficacy of regorafenib in combination with chemotherapy. At this point in time, regorafenib is the first small-molecule tyrosine kinase inhibitor to gain approval by the US Food and Drug Administration for pretreated metastatic colorectal cancer patients.

Efficacy of a protocol including heparin ointment for treatment of multikinase inhibitor-induced hand–foot skin reactions

The purpose of this study is to evaluate the efficacy of a protocol including topical heparin therapy for hand-foot skin reactions (HFSR) during multikinase (MKI) treatment. We prospectively collected 26 patients who had HFSRs during treatment with the MKIs, sunitinib, sorafenib, or axitinib. The age distribution ranged from 46 to 87 years, with a mean of 66 years. The distribution of HFSR severity was 12 patients with grade 1, 12 with grade 2, and 2 with grade 3. A heparin-containing topical ointment treatment, combined with hand-foot shock absorbers and skin moisturizers, was used at the lesion sites. Changes in the grade of HFSR, MKI dosage, and interruptions of MKI therapy were recorded. The results showed that 66.7% of grade 1 patients were cured of disease, 83.3% of grade 2 patients had improved symptoms, and both grade 3 patients (100%) had improved symptoms and were downgraded to grade 2. Four (15.4%) patients required reduction of MKI dosage, but there were no treatment interruptions or dropouts. Our protocol is beneficial in promoting resolution of HFSRs induced by MKIs. Further validation in large control studies should be investigated.

Overcoming chemotherapy resistance in patients (pts) with chemotherapy-failure, castration-resistant prostate cancer (CRPC) with sorafenib.

127 Background: SOR is an oral multi kinase inhibitor that promotes apoptosis through downstream pathways that can be deregulated in CRPC leading to chemotherapy resistance. We hypothesized that SOR Could overcome chemotherapy resistance in non-responders or in those who progress shortly after stopping chemotherapy. Methods: Eligible pts were those who progressed while receiving chemotherapy [docetaxel (D) or mitoxantrone (M)] or within 12 weeks from stopping it. Pts were then continued or resumed on their last chemotherapy with the addition of SOR at 400 mg PO BID. Pts were allowed a maximum of 6 cycles of chemotherapy +SOR followed by SOR as monotherapy until progression. Primary end point: Safety of SOR+ chemotherapy. Secondary end points: Toxicity, time to progression (TTP). And responses (biochemical and radiographic) Results: Twenty-two pts were enrolled; 21 evaluable (73% Gleason ≥ 7). Median age was 68 (59-83). Median PSA was 142 ng/dl (13.6-9,584). Median time from last chemotherapy to SOR was 4 weeks. Visceral and bone disease was present in 64%. D was given in 16 pts while M in 6. Ten pts (45%) showed biochemical response (18% with &gt;50% PSA decline). Despite progression before being on study, 16 pts (76%) achieved SD after starting SOR for a median duration of 6 months (4-12). The combination of SOR with either chemotherapy agent proved safe. Main grade 3/4 non-hematologic toxicities: Fatigue 7 (32%), 4 (18%) hand/foot syndrome, hypocalcemia and hyperglycemia in 2 pts (9%) each. Grade 3/4 leukopenia was seen in 7 (31%), neutropenia in 6 (27%), and thrombocytopenia in 2 (9%). Dose reduction of SOR occurred at least once in 15 pts (68%). Major reasons are hand/foot syndrome (22%), fatigue (22%), rash (13%), and neutropenia (9%). With a median follow-up of 19 months (3-46), 5 pts (23%) remain alive for a median OS of 8 months. TTP by PSA was 3 months (2-6) and TTP by imaging and/or clinically was 6 months (2-12). Median number of treatment cycles given was 6 (1-10). Conclusions: SOR can safely be combined with chemotherapy. SOR overcomes chemotherapy-resistance and shows biochemical and radiographic stability in this refractory pt population.

Plasma protein binding of sorafenib, a multi kinase inhibitor: in vitro and in cancer patients

Sorafenib is an orally administered multikinase inhibitor that exhibits antiangiogenic and antitumor activity. Few investigators have been able to correlate cumulative sorafenib dose or total exposure to pharmacodynamic effects. This discrepancy may be in part due to poorly understood protein binding characteristics. Since unbound drug concentrations are believed to be more relevant to pharmacological and toxicological responses than total drug, an equilibrium dialysis method using 96-well microdialysis plates was optimized and validated for determining the fraction unbound (F(u)) sorafenib in human plasma and in isolated protein solutions. Unbound sorafenib concentrations were determined in cancer patients receiving the drug orally at a dose of 400 mg and 600 mg twice daily. Sorafenib was extensively bound with mean F(u) value of 0.3% in both non-cancer and cancer patient's plasma. The binding in plasma was concentration independent, indicating a low-affinity, possibly nonspecific and nonsaturable process. In isolated protein solutions, 99.8% and 79.3% of sorafenib was bound to human serum albumin (HSA) (4 g/dL) and α(1)-acid glycoprotein (AAG) (0.1 g/dL) with binding constants of 1.24 × 10(6) M(-1) and 1.40 × 10(5) M(-1), respectively. In cancer patients receiving sorafenib, unbound sorafenib was not correlated with patient characteristics or laboratory values. In conclusion, sorafenib is highly protein bound in human plasma with a higher affinity towards albumin and limited free drug may be partly responsible for its borderline clinical activity.

Abstract 3605: KW-2450, a novel orally-active dual IGF1R/IR inhibitor: Antitumor effects in vitro and in vivo

Abstract KW-2450 is an orally active, multi-kinase inhibitor which inhibits both insulin-like growth factor receptor (IGF-1R) and insulin receptor (IR) with an IC50 of 7.39 nmol/L and 5.64 nmol/L, respectively. KW-2450 also exhibits inhibitory activities (&amp;gt;90% at 100 nmol/L) against several protein tyrosine kinases such as FAK, FLT1, FLT3, JAK2, KDR, TRKA, and Aurora A. KW-2450 inhibited the growth of various types of malignant cells, and the reduction of phosphorylated IGF-1R or IR and their downstream signalling such as phosphorylation of AKT and ERK were observed from 10 to 30 nmol/L in vitro. The PK/PD study of KW-2450 was conducted in a human colon cancer HT-29/GFP xenograft model. The plasma concentrations of KW-2450 were measured by LC/MS/MS method and the phosphorylation status of IGF-1R (P-IGF-1R) and AKT (P-AKT) in tumor tissue were examined by Western blotting. A single oral administration of KW-2450 showed inhibition of P-IGF-1R and P-AKT in tumor tissue in accordance with the increasing plasma concentration and peaked 2 hours after the administration of the drug at doses of 10 to 80 mg/kg. In this model, KW-2450 showed a statistically significant suppression of tumor growth by oral administration at a dose of 40 mg/kg once a day for 14 days. In addition, KW-2450 at a dose of 10 mg/kg showed a potent growth inhibitory activity against a human myeloma KMS-12-BM xenograft model, which is sensitive to the compound in vitro. In mice, KW-2450 induced an increase of plasma glucose levels at 20 mg/kg and higher in a dose-dependent manner. However, the increase in glucose was transient and it returned to normal levels within 2 hours at 20 mg/kg, 4 hours at 40 mg/kg and 8 hours at 80 mg/kg. A similar trend was seen in insulin levels which return to normal levels within 4 hours at 10 mg/kg, 8 hours at 20 and 40 mg/kg, and 24 hours at 80 mg/kg. In summary, these pharmacological studies revealed that KW-2450 could act as a potent and selective dual IGF-1R/IR inhibitor and exert antitumor effects on various types of malignant cells in vitro and in vivo, although this compound shows multi kinase inhibitory activity in a cell free system. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3605. doi:10.1158/1538-7445.AM2011-3605

Abstract 3579: Sorafenib inhibits tumor development and growth in a transgenic mouse model of prostate cancer

Abstract Background: Current estimates suggest that PI3K/Akt/mTOR signaling is upregulated in 30-50% of prostate cancers (PCa), namely through loss of Pten. Although Ras mutations in prostate cancer are infrequent, wild-type Ras is chronically activated in PCa as a result of autocrine and paracrine growth factor stimulation. More recently, it has been demonstrated that Ras activation can play a causal role in moving PCa cells towards decreased hormone dependence and an increased malignant phenotype. Sorafenib is a small molecule multikinase inhibitor that disrupts angiogenesis and blocks signaling pathways through multiple kinases, including c-Raf, that control tumor growth and progression. The purpose of this study was to evaluate the efficacy of the multi kinase inhibitor sorafenib in an autochthonous mouse model of PCa. Methods: Homozygous PSACre;PtenloxP/loxP mice were used and treated with sorafenib in chemoprevention (30 mg/kg, 3/wk for 9 or 16 wks beginning at 6 wks) and intervention (30 or 60 mg/kg 5/wk for 4 wks beginning at 16 wks) treatment protocols for androgen dependent PCa and castrate resistant prostate cancer (CRPC). Tumor size was measured by weighing the genitourinary tracts (GUT) and tumor progression was assessed by histological and computer assisted image analysis. Tumor proliferation and cell signaling was determined by immunohistochemical and/or western blot methods. Apoptosis was measured using the TUNEL method. Results: To determine the chemopreventive efficacy of sorafenib, mice were treated prior tumor development and sacrificed at time points that correlated to the different stages of tumor development (15 and 20 wks of age). Mice treated with sorafenib had significantly lower GUT weights at week 20 compared to untreated controls, (p&amp;lt;0.005). Moreover, mice treated with sorafenib showed a decrease in the number of PCa glands and an increase in PIN (prostatic intraepithelial neoplasia) glands compared to controls. To determine the effects of sorafenib on established tumors, mice with prostate cancer were treated with sorafenib in a dose dependent manner. Mice showed a non-significant but dose dependent reduction of GUT weight in mice treated with sorafenib. However, distribution analysis demonstrated a significant reduction of over 50% of PCa glands in sorafenib treated mice (p &amp;lt; 0.009). Treatment with sorafenib contributed to a 50% reduction in tumor proliferation and a 4-fold increase in apoptosis (p&amp;lt;0.005). In CRPC mice treated with sorafenib, a significant reduction in GUT weights, PCa glands and tumor proliferation and an increase in apoptosis were seen (p&amp;lt;0.01). p-Erk1/2 expression was markedly reduced in all mice treated with sorafenib when measured by immunohistochemistry and western blot. Conclusion: Taken together, these results suggest that treatment with sorafenib results in decreased prostate tumor growth and progression, particularly in tumors with Pten mutations. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 3579. doi:10.1158/1538-7445.AM2011-3579

Development of a Cell-Selective and Intrinsically Active Multikinase Inhibitor Bioconjugate

Multikinase inhibitors are potent anticancer drugs that simultaneously intervene in multiple related signaling cascades, thus being capable of blocking salvage pathways that may play a role in the development of drug resistance. Multikinase inhibitors are increasingly evaluated for indications other than cancer, but long-term safety risks dictated by off-organ toxicities of these agents may prevent their safe and effective use. Here, we describe a new approach in which platinum coordination chemistry is applied for the development of a cell-selective multikinase inhibitor bioconjugate. The platinum(II) kinase inhibitor bioconjugate was designed to be active with the linker attached to the inhibitor and displayed improved activity by enhanced cell specificity as well as enhanced intracellular retention, thereby prolonging its pharmacological activity. In addition, the utilized platinum-based linkage technology potentiated the inhibitory activity of the multikinase inhibitor. These features in combination with carrier-mediated uptake in the target cells may revolutionize dosing regimens and safety profiles of (multi)kinase inhibitors.