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Purpose Everolimus is a mammalian target of rapamycin (mTOR) inhibitor approved as an immunosuppressant and for second-line therapy of hepatocellular carcinoma (HCC) and renal cell carcinoma (RCC). Sorafenib is a multikinase inhibitor used as first-line therapy in HCC and RCC. This study assessed the pharmacokinetics (PK) of everolimus and sorafenib alone and in combination in plasma and tissues, developed physiologically based pharmacokinetic (PBPK) models in mice, and assessed the possibility of PK drug interactions. Methods Single and multiple oral doses of everolimus and sorafenib were administered alone and in combination in immunocompetent male mice and to severe combined immune-deficient (SCID) mice bearing low-passage, patient-derived pancreatic adenocarcinoma in seven different studies. Plasma and tissue samples including tumor were collected over a 24-h period and analyzed by liquid chromatography-tandem mass spectrometry (LC–MS/MS). Distribution of everolimus and sorafenib to the brain, muscle, adipose, lungs, kidneys, pancreas, spleen, liver, GI, and tumor was modeled as perfusion rate-limited, and all data from the diverse studies were fitted simultaneously using a population approach. Results PBPK models were developed for everolimus and sorafenib. PBPK analysis showed that the two drugs in combination had the same PK as each drug given alone. A twofold increase in sorafenib dose increased tumor exposure tenfold, thus suggesting involvement of transporters in tumor deposition of sorafenib. Conclusions The developed PBPK models suggested the absence of PK interaction between the two drugs in mice. These studies provide the basis for pharmacodynamic evaluation of these drugs in patient-derived primary pancreatic adenocarcinomas explants.

Purpose Molecular targeting of cellular signaling pathways is a promising approach in cancer therapy, but often fails to achieve sustained benefit because of the activation of collateral cancer cell survival and proliferation pathways. We tested the hypothesis that a combination of targeted agents that inhibit compensatory pathways would be more effective than single agents in controlling pancreatic cancer cell growth. We investigated whether everolimus, an mTOR inhibitor, and sorafenib, a multi-kinase inhibitor, would together inhibit growth of low-passage, patient-derived pancreatic cancer xenografts in mice more efficaciously than either agent alone. Methods Tumor volume progression was measured following treatment with both drugs as single agents, in combination, and at multiple doses. Pharmacokinetics in tumors and other tissues was also assessed. Pharmacodynamic interactions were evaluated quantitatively. Results A 5-week regimen of daily oral doses of 10 mg/kg sorafenib and 0.5 mg/kg everolimus, alone and in combination, did not achieve significant tumor growth inhibition. Higher doses (20 mg/kg of sorafenib and 1 mg/kg of everolimus) inhibited tumor growth significantly when given alone and caused complete inhibition of growth when given in combination. Tumor volume progression was described by a linear growth model, and drug effects were described by Hill-type inhibition. Using population modeling approaches, dual-interaction parameter estimates indicated a highly synergistic pharmacodynamic interaction between the two drugs. Conclusions The results indicate that combinations of mTOR and multi-kinase inhibitors may offer greater efficacy in pancreatic cancer than either drug alone. Drug effects upon tumor stromal elements may contribute to the enhanced anti-tumor efficacy.

BackgroundThere has been a dramatic increase in T cell receptor (TCR) sequencing spurred, in part, by the widespread adoption of this technology across academic medical centers and by the rapid commercialization of TCR sequencing. While the raw TCR sequencing data has increased, there has been little in the way of approaches to parse the data in a biologically meaningful fashion. The ability to parse this new type of 'big data' quickly and efficiently to understand the T cell repertoire in a structurally relevant manner has the potential to open the way to new discoveries about how the immune system is able to respond to insults such as cancer and infectious diseases.

Introduction. FGF signaling has been implicated in pancreatic cancer (PC) tumorigenesis and tumor-stromal interactions. Dovitinib is a potent inhibitor of the FGF receptors. We examined the effect of dovitinib in pancreatic cancer in relation to tumor FGFR2 expression using cell lines and patient-derived primary PC models. Methods. FGFR2 expression in 6 PC cell lines (L3.6PL, Panc4.30, AsPC1, Panc2.13, SU86.86, Panc02.03) and 13 patient-derived primary PC tumors was assessed using immunoblotting and RT-PCR. Dovitinib efficacy was assessed in vitro following FGF2 stimulation (IC50 < 10 μM). Contribution by FGF signaling inhibition was evaluated by knockdown and constitutive activation of FRS2, Mcl-1 and Akt. Effects on downstream signaling pathways were evaluated by immunoblotting. Tumor-bearing mice were treated with dovitinib 40mg/kg (daily oral gavage) and tumor growth was measured. Effects of dovitinib in tumors were evaluated by immunohistochemistry (H&E, ki67, TUNEL, CD34, aSMA, collagen IV). Results. Dovitinib and FRS2 shRNA induced significant in vitro cell kill in bFGF-stimulated PC cell lines that had elevated FGFR2 mRNA expression. This was associated with inhibition of p-Akt and decreased Mcl-1 level in sensitive PC cells. Ectopic Mcl-1 and constitutively active Akt1 overexpression reversed the sensitivity whereas Mcl-1 knockdown sensitized resistant PC cells to dovitinib-induced apoptosis. In in vivo xenograft studies, compared to controls, dovitinib caused significant growth inhibition in high FGFR2 mRNA expressing PC (L3.6PL; T/C=0 after 10 days) but not low expressing PC (SU86.86; T/C=0.8 after 28 days). We then selected a primary tumor with high FGFR2 mRNA expression (#12424), which dovitinib exerted anti-proliferative and pro-apoptotic effects, causing significant growth inhibition (T/C=0.1 after 28 days), with reduced tumor-associated stroma and microvessel density at ≤ 20 mg/kg in a dose-dependent manner. Dovitinib caused only moderate tumor growth inhibition in #10978 (T/C= 0.78), a low FGFR2 mRNA expressing primary tumor. Conclusions. Dovitinib demonstrated significant anti-tumor efficacy that was mediated via the Akt/Mcl-1 pathway, and this effect was dependent on FGFR2 activity. We propose that FGFR2 mRNA level may be a predictive marker for efficacy of dovitinib in PC, and will be evaluated in an on-going clinical trial using a dovitinib-containing regimen. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1214. doi:1538-7445.AM2012-1214