Purpose: Given that histone deacetylase (HDAC) inhibitors are known to induce multiple epigenetic modifications affecting signaling networks and act synergistically with phosphatidylinositol 3-kinase (PI3K) inhibitors, we developed a strategy to simultaneously inhibit HDACs and PI3K in cancer cells.Experimental Design: We constructed dual-acting inhibitors by incorporating HDAC inhibitory functionality into a PI3K inhibitor pharmacophore. CUDC-907, a development candidate selected from these dual inhibitors, was evaluated in vitro and in vivo to determine its pharmacologic properties, anticancer activity, and mechanism of action.Results: CUDC-907 potently inhibits class I PI3Ks as well as classes I and II HDAC enzymes. Through its integrated HDAC inhibitory activity, CUDC-907 durably inhibits the PI3K-AKT-mTOR pathway and compensatory signaling molecules such as RAF, MEK, MAPK, and STAT-3, as well as upstream receptor tyrosine kinases. CUDC-907 shows greater growth inhibition and proapoptotic activity than single-target PI3K or HDAC inhibitors in both cultured and implanted cancer cells.Conclusions: CUDC-907 may offer improved therapeutic benefits through simultaneous, sustained disruption of multiple oncogenic signaling networks. Clin Cancer Res; 18(15); 4104-13. Ó2012 AACR.

By incorporating histone deacetylase (HDAC) inhibitory functionality into the pharmacophore of the epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) inhibitors, we synthesized a novel series of compounds with potent, multiacting HDAC, EGFR, and HER2 inhibition and identified 7-(4-(3-ethynylphenylamino)-7-methoxyquinazolin-6-yloxy)-N-hydroxyheptanamide 8 (CUDC-101) as a drug candidate, which is now in clinical development. 8 displays potent in vitro inhibitory activity against HDAC, EGFR, and HER2 with an IC(50) of 4.4, 2.4, and 15.7 nM, respectively. In most tumor cell lines tested, 8 exhibits efficient antiproliferative activity with greater potency than vorinostat (SAHA), erlotinib, lapatinib, and combinations of vorinostat/erlotinib and vorinostat/lapatinib. In vivo, 8 promotes tumor regression or inhibition in various cancer xenograft models including nonsmall cell lung cancer (NSCLC), liver, breast, head and neck, colon, and pancreatic cancers. These results suggest that a single compound that simultaneously inhibits HDAC, EGFR, and HER2 may offer greater therapeutic benefits in cancer over single-acting agents through the interference with multiple pathways and potential synergy among HDAC and EGFR/HER2 inhibitors.

Receptor tyrosine kinase inhibitors have recently become important therapeutics for a variety of cancers. However, due to the heterogeneous and dynamic nature of tumors, the effectiveness of these agents is often hindered by poor response rates and acquired drug resistance. To overcome these limitations, we created a novel small molecule, CUDC-101, which simultaneously inhibits histone deacetylase and the receptor kinases epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) in cancer cells. Because of its integrated histone deacetylase inhibition, CUDC-101 synergistically blocked key regulators of EGFR/HER2 signaling pathways, also attenuating multiple compensatory pathways, such as AKT, HER3, and MET, which enable cancer cells to escape the effects of conventional EGFR/HER2 inhibitors. CUDC-101 displayed potent antiproliferative and proapoptotic activities against cultured and implanted tumor cells that are sensitive or resistant to several approved single-targeted drugs. Our results show that CUDC-101 has the potential to dramatically improve the treatment of heterogeneous and drug-resistant tumors that cannot be controlled with single-target agents. Further, they provide a framework to create individual small molecules that simultaneously antagonize multiple biochemically distinct oncogenic targets, suggesting a general paradigm to surpass conventional, single-target cancer therapeutics. Cancer Res; 70(9); 3647-56. ©2010 AACR.

Our analysis identified several clinicopathologic factors associated with AL in patients who underwent LAR. The knowledge of these risk factors may influence treatment- and procedure-related decisions and possibly reduce the leakage rate.

Immunological unresponsiveness established by the elimination or anergy of self-reactive lymphocyte clones is of importance to immunization against tumorassociated antigens. In this study, we have investigated induction of immunity against the human MUC1 carcinomaassociated antigen in MUC1 transgenic mice unresponsive to The human DF3͞MUC1 glycoprotein is overexpressed and aberrantly glycosylated in breast and other carcinomas (1-4). The finding that lymphocytes from certain patients with carcinomas recognize and lyse MUC1-positive tumor cells (5, 6) has suggested that this antigen is a potential target for anticancer vaccines. Whereas MUC1 is expressed on the apical borders of normal epithelium (1-3) and unresponsiveness to self-antigens is an obstacle to the development of antitumor immunity, MUC1 transgenic (MUC1.Tg) mice provide a potential model to assess the induction of anti-MUC1 immune responses. In this context, MUC1.Tg C57BL6 mice express MUC1 in a pattern and at a level similar to that found in humans (7). Significantly, the MUC1.Tg mice are tolerant to stimulation by MUC1 antigen (7).Dendritic cells (DC) are potent antigen-presenting cells (8) that sensitize CD4 ϩ T cells to specific antigens in a major histocompatibility complex-restricted manner (9, 10) and generate antigen-specific cytotoxic T lymphocytes (CTLs) from naive T cells in vitro (11,12). Moreover, DCs are the only antigen-presenting cells known to prime naive CTLs and to induce antigen-specific CTLs in vivo (13). DCs pulsed with tumor antigens or synthetic peptides derived from such antigens have been effective as vaccines in the induction of CTL responses and antitumor activity (14)(15)(16)(17). Other studies have demonstrated that transduction of DC with recombinant viral vectors expressing tumor antigens generates vaccines that induce antigen-specific antitumor immune responses (18)(19)(20). Fusions resulting in heterokaryons of DC and carcinoma cells as vaccines have provided an alternative strategy for inducing immunity against both known and unidentified tumor antigens (21).The present studies demonstrate that MUC1.Tg mice respond to fusions of DC and MUC1-positive MC-38 carcinoma cells with induction of anti-MUC1 immunity. The findings demonstrate that a DC fusion cell vaccine can reverse unresponsiveness to a tumor-associated antigen and induce the rejection of established metastases. MATERIALS AND METHODS MUC1 Transgenic Mice.A C57BL͞6 mouse strain transgenic for human MUC1 was established as described (7). Tail DNA (500 ng) was subjected to PCR amplification by using MUC1 primers (bp 745-765 and bp 1,086-1,065) to confirm the presence of MUC1 sequences. The PCR product was detected by electrophoresis in a 1% agarose gel (7).Cell Culture and Fusion. Murine (C57BL͞6) MC-38 and MB49 carcinoma cells were stably transfected with a MUC1 cDNA (22-24). Cells were maintained in DMEM supplemented with 10% heat-inactivated fetal calf serum, 2 mM

Purpose: We designed and synthesized CUDC-305, an HSP90 inhibitor of the novel imidazopyridine class. Here, we report its unique pharmacologic properties and antitumor activities in a variety of tumor types. Experimental Design: The potency of the compound was analyzed by fluorescence polarization competition binding assay. Its antiproliferative activities were assessed in 40 human cancer cell lines. Its pharmacologic properties and antitumor activities were evaluated in a variety of tumor xenograft models.Results: CUDC-305 shows high affinity for HSP90α/β (IC 50 , ∼100 nmol/L) and HSP90 complex derived from cancer cells (IC 50 , 48.8 nmol/L). It displays potent antiproliferative activity against a broad range of cancer cell lines (mean IC 50 , 220 nmol/L). CUDC-305 exhibits high oral bioavailability (96.0%) and selective retention in tumor (half-life, 20.4 hours) compared with normal tissues. Furthermore, CUDC-305 can cross bloodbrain barrier and reach therapeutic levels in brain tissue. CUDC-305 exhibits dosedependent antitumor activity in an s.c. xenograft model of U87MG glioblastoma and significantly prolongs animal survival in U87MG orthotopic model. CUDC-305 also displays potent antitumor activity in animal models of erlotinib-resistant non-small cell lung cancer and induces tumor regression in animal models of MDA-MB-468 breast cancer and MV4-11 acute myelogenous leukemia. Correlating with its efficacy in these various tumor models, CUDC-305 robustly inhibits multiple signaling pathways, including PI3K/AKT and RAF/MEK/ERK, and induces apoptosis. In combination studies, CUDC-305 enhances the antitumor activity of standard-of-care agents in breast and colorectal tumor models. Conclusion: CUDC-305 is a promising drug candidate for the treatment of a variety of cancers, including brain malignancies.

No abstract

The number of patients with non-human immunodeficiency virus (HIV) related pneumocystis carinii pneumonia (PCP) is increasing with widespread immunosuppressive treatment. We performed a meta-analysis to describe the clinical characteristics and factors associated with outcomes of PCP in HIV-negative patients. A total of 13 studies including 867 patients with non-HIV related PCP was included. The overall mortality for non-HIV patients with PCP was 30.6%. The most common underlying disorder for the development of PCP is hematological malignancies (29.1%), followed by autoimmune disease (20.1%), organ or bone marrow transplantation (14.0%), and solid tumors (6.0%). Risk factors associated with increased mortality rate including old age, female sex, longer time from onset of symptoms to diagnosis, respiratory failure, solid tumors, high lactate dehydrogenase, low serum albumin, bacterial, and aspergillus co-infection, etc (P < 0.05). Adjunctive corticosteroid and PCP prophylaxis was not shown to improve the outcome of PCP in non-HIV patients (P > 0.05). Our findings indicate that mortality in non-HIV patients with PCP is high. Improved knowledge about the prognostic factors may guide the early treatment.