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Suttle A.B.,Glaxosmithkline | Ottesen L.H.,Glaxosmithkline | Lenz H.-J.,University of Southern California | Kummar S.,U.S. National Cancer Institute | And 11 more authors.
Clinical Cancer Research | Year: 2013

Purpose: Pazopanib is a potent, multitargeted receptor tyrosine kinase inhibitor; however, there is limited information regarding the effects of liver function on pazopanib metabolism and pharmacokinetics. The objective of this study was to establish the maximum-tolerated dose (MTD) and pharmacokinetic profile of pazopanib in patients with varying degrees of hepatic dysfunction. Experimental Design: Patients with any solid tumors or lymphoma were stratified into four groups based on the degree of hepatic dysfunction according to the National Cancer Institute Organ Dysfunction Working Group (NCI-ODWG) criteria. Pazopanib was given orally once a day on a 21-day cycle. A modified 33 design was used. Results: Ninety-eight patients were enrolled. Patients in the mild group tolerated 800 mg per day. The moderate and severe groups tolerated 200 mg per day. Pharmacokinetic data in the mild group were similar to the data in the normal group. Comparison of the median Cmax and area under the curve [AUC(0-24) ] in the moderate or severe groups at 200 mg per day to the values in the normal and mild groups at 800 mg per day indicated less than dose-proportional systemic exposures in patients with moderate and severe hepatic impairment. This suggests that the lower maximum-tolerated dose in the moderate and severe group is not due to a decrease in drug clearance or alteration in the proportion of metabolites. Conclusions: In patients with mild liver dysfunction, pazopanib is well tolerated at the Food and Drug Administration (FDA)-approved dose of 800 mg per day. Patients with moderate and severe liver dysfunction tolerated 200 mg per day. ©2013 AACR.

Wang Q.,University of Houston | Wang Q.,Shanghai JiaoTong University | Li S.-H.,University of Houston | Wang H.,University of Houston | And 9 more authors.
Cancer Research | Year: 2012

Trastuzumab is an iconic rationally designed targeted therapy for HER2-positive breast cancers. However, the low response rate and development of resistance call for novel approaches for the treatment of patients. Here, we report that concurrent targeting of tumor cells and activation of T cells in the tumor microenvironment results in a synergistic inhibitory effect on tumor growth and overcomes resistance in two distinct PTEN loss-mediated trastuzumab-resistant mammary tumor mouse models. In vivo combination treatment with HER2/Neu antibody and Akt inhibitor triciribine effectively inhibited tumor growth in both models via inhibiting PI3K/AKT and mitogen-activated protein kinase signaling accompanied by increased T-cell infiltration in the tumor microenvironment. We showed that both CD8+ and CD4+ T cells were essential to the optimal antitumor effect of this combination treatment in an IFNγ-dependent manner. Importantly, the antitumor activities of HER2/Neu antibody and triciribine combination treatment were further improved when coinhibitory receptor cytotoxic T-lymphocyte-associated antigen 4 was blocked to enhance the T-cell response. Our data indicate that multitargeted combinatorial therapies targeting tumor cells and concomitantly enhancing T-cell response in the tumor microenvironment could cooperate to exert maximal therapeutic activity, suggesting a promising clinical strategy for treating trastuzumab-resistant breast cancers and other advanced malignancies. ©2012 AACR.

Ambinder R.F.,Sidney Kimmel Cancer Center at Johns Hopkins | Bhatia K.,U.S. National Cancer Institute | Martinez-Maza O.,University of California at Los Angeles | Mitsuyasu R.,University of California at Los Angeles
Current Opinion in HIV and AIDS | Year: 2010

Purpose of Review: In this review, we update investigations related to cancer biomarkers in HIV-infected populations. Recent Findings: CD4 lymphocyte count is associated with primary central nervous system lymphoma (PCNSL), systemic non-Hodgkin's lymphoma (NHL) (except perhaps for Burkitt lymphoma), Kaposi's sarcoma, cervical cancer, and anal cancer. HIV load is associated with Burkitt lymphoma and systemic NHL (but not PCNSL), with Kaposi's sarcoma and with anal cancer. CD40 ligand incorporated into the HIV envelope and expression of activation-induced cytidine deaminase may help explain the relationship between HIV load and Burkitt lymphoma. Genetic polymorphisms have been identified that are linked to lymphoma in HIV patients. B-cell activation as manifest in immunoglobulin light chain production may be an important marker for NHL risk. Cytokines and related molecules (IL10, sCD30) may identify patients at high risk for NHL. Epstein-Barr virus (EBV) in cerebrospinal fluid (CSF) is useful as a marker for PCNSL, although with the falling incidence of PCNSL, the specificity of the test has been called into question. EBV and Kaposi's sarcoma-associated herpesvirus (KSHV) have not yet emerged as especially promising markers of risk for either lymphoma or Kaposi's sarcoma. Summary: CD4 lymphocyte count, HIV load, germline genetic polymorphisms, cytokine and related molecules, and immunoglobulin light chains all show increasing promise as biomarkers of malignancy in HIV patients. © 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins.

Parry D.,Merck And Co. | Parry D.,Portola Pharmaceuticals, Inc. | Hess A.D.,Sidney Kimmel Cancer Center at Johns Hopkins | Smith B.D.,Sidney Kimmel Cancer Center at Johns Hopkins | And 3 more authors.
Clinical Cancer Research | Year: 2012

Purpose: Previous studies have shown that the replication checkpoint, which involves the kinases ataxia telangiectasia mutated and Rad3 related (ATR) and Chk1, contributes to cytarabine resistance in cell lines. In the present study, we examined whether this checkpoint is activated in clinical acute myelogenous leukemia (AML) during cytarabine infusion in vivo and then assessed the impact of combining cytarabine with the recently described Chk1 inhibitor SCH 900776 in vitro. Experimental design: AML marrow aspirates harvested before and during cytarabine infusion were examined by immunoblotting. Human AML lines treated with cytarabine in the absence or presence of SCH 900776 were assayed for checkpoint activation by immunoblotting, nucleotide incorporation into DNA, and flow cytometry. Long-term effects in AML lines, clinical AML isolates, and normal myeloid progenitors were assayed using clonogenic assays. Results: Immunoblotting revealed increased Chk1 phosphorylation, a marker of checkpoint activation, in more than half of Chk1-containing AMLs after 48 hours of cytarabine infusion. In human AML lines, SCH 900776 not only disrupted cytarabine-induced Chk1 activation and S-phase arrest but also markedly increased cytarabine-induced apoptosis. Clonogenic assays demonstrated that SCH 900776 enhanced the antiproliferative effects of cytarabine in AML cell lines and clinical AML samples at concentrations that had negligible impact on normal myeloid progenitors. Conclusions: These results not only provide evidence for cytarabine-induced S-phase checkpoint activation in AML in the clinical setting, but also show that a selective Chk1 inhibitor can overcome the S-phase checkpoint and enhance the cytotoxicity of cytarabine. Accordingly, further investigation of the cytarabine/SCH 900776 combination in AML appears warranted. ©2012 AACR.

Gupta M.,Mayo Medical School | Wahner Hendrickson A.E.,Mayo Medical School | Yun S.S.,Mayo Medical School | Han J.J.,Mayo Medical School | And 16 more authors.
Blood | Year: 2012

The mammalian target of rapamycin (mTOR) plays crucial roles in proliferative and antiapoptotic signaling in lymphoid malignancies. Rapamycin analogs, which are allosteric mTOR complex 1 (mTORC1) inhibitors, are active in mantle cell lymphoma and other lymphoid neoplasms, but responses are usually partial and short-lived. In the present study we compared the effects of rapamycin with the dual mTORC1/mTORC2 inhibitor OSI-027 in cell lines and clinical samples representing divers lymphoid malignancies. In contrast to rapamycin, OSI-027 markedly diminished proliferation and induced apoptosis in a variety of lymphoid cell lines and clinical samples, including specimens of B-cell acute lymphocytic leukemia (ALL), mantle cell lymphoma, marginal zone lymphoma and Sezary syndrome. Additional analysis demonstrated that OSI-027-induced apoptosis depended on transcriptional activation of the PUMA and BIM genes. Overexpression of Bcl-2, which neutralizes Puma and Bim, or loss of procaspase 9 diminished OSI-027-induced apoptosis in vitro. Moreover, OSI-027 inhibited phosphorylation of mTORC1 and mTORC2 substrates, upregulated Puma, and induced regressions in Jeko xenografts. Collectively, these results not only identify a pathway that is critical for the cytotoxicity of dual mTORC1/mTORC2 inhibitors, but also suggest that simultaneously targeting mTORC1 and mTORC2 might be an effective anti-lymphoma strategy in vivo. © 2012 by The American Society of Hematology.

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