MET Copy Number Gain Is Associated with Gefitinib Resistance in Leptomeningeal Carcinomatosis of EGFR-mutant Lung Cancer
This study aimed to clarify the mechanism of EGFR-TKI resistance in leptomeningeal carcinomatosis and seek for a novel therapeutic strategy. We examined EGFR mutations, including the T790M gatekeeper mutation, in 32 re-biopsy specimens from 12 leptomeningeal carcinomatosis and 20 extracranial lesions of EGFR-mutant lung cancer patients who became refractory to EGFR-TKI treatment. All the 32 specimens had the same baseline EGFR mutations, but the T790M mutation was less frequent in leptomeningeal carcinomatosis specimens than in extracranial specimens (8% vs. 55%, P < 0.01). To study molecular mechanisms of acquired EGFR...
Source: Molecular Cancer Therapeutics - March 1, 2017 Category: Cancer & Oncology Authors: Nanjo, S., Arai, S., Wang, W., Takeuchi, S., Yamada, T., Hata, A., Katakami, N., Okada, Y., Yano, S. Tags: Cancer Biology and Signal Transduction Source Type: research
Bone-Seeking Matrix Metalloproteinase-2 Inhibitors Prevent Bone Metastatic Breast Cancer Growth
Bone metastasis is common during breast cancer progression. Matrix metalloproteinase-2 (MMP-2) is significantly associated with aggressive breast cancer and poorer overall survival. In bone, tumor- or host-derived MMP-2 contributes to breast cancer growth and does so by processing substrates, including type I collagen and TGFβ latency proteins. These data provide strong rationale for the application of MMP-2 inhibitors to treat the disease. However, in vivo, MMP-2 is systemically expressed. Therefore, to overcome potential toxicities noted with previous broad-spectrum MMP inhibitors (MMPIs), we used highly selective b...
Source: Molecular Cancer Therapeutics - March 1, 2017 Category: Cancer & Oncology Authors: Tauro, M., Shay, G., Sansil, S. S., Laghezza, A., Tortorella, P., Neuger, A. M., Soliman, H., Lynch, C. C. Tags: Cancer Biology and Signal Transduction Source Type: research
Dual Inhibition of Key Proliferation Signaling Pathways in Triple-Negative Breast Cancer Cells by a Novel Derivative of Taiwanin A
In this study, we report that 3,4-bis-3,4,5-trimethoxybenzylidene-dihydrofuran (BTMB), a novel derivative of Taiwanin A, significantly inhibited the proliferation of triple-negative breast cancer (TNBC) cells both in vitro and in vivo. The results show that BTMB inhibited the proliferation of human TNBC cells by the induction of cell-cycle arrest and apoptosis in a dose-dependent fashion. BTMB inhibited the expression of β-catenin, cdc2 and the cell-cycle regulatory proteins, cyclin A, cyclin D1, and cyclin E. The mechanism of action was associated with the suppression of cell survival signaling through inactivation o...
Source: Molecular Cancer Therapeutics - March 1, 2017 Category: Cancer & Oncology Authors: Kuo, Y.-H., Chiang, E.-P. I., Chao, C.-Y., Rodriguez, R. L., Chou, P.-Y., Tsai, S.-Y., Pai, M.-H., Tang, F.-Y. Tags: Small Molecule Therapeutics Source Type: research
Targeting Plk1 to Enhance Efficacy of Olaparib in Castration-Resistant Prostate Cancer
Olaparib is an FDA-approved PARP inhibitor (PARPi) that has shown promise as a synthetic lethal treatment approach for BRCA-mutant castration-resistant prostate cancer (CRPC) in clinical use. However, emerging data have also shown that even BRCA-mutant cells may be resistant to PARPi. The mechanistic basis for these drug resistances is poorly understood. Polo-like kinase 1 (Plk1), a critical regulator of many cell-cycle events, is significantly elevated upon castration of mice carrying xenograft prostate tumors. Herein, by combination with Plk1 inhibitor BI2536, we show a robust sensitization of olaparib in 22RV1, a BRCA1-...
Source: Molecular Cancer Therapeutics - March 1, 2017 Category: Cancer & Oncology Authors: Li, J., Wang, R., Kong, Y., Broman, M. M., Carlock, C., Chen, L., Li, Z., Farah, E., Ratliff, T. L., Liu, X. Tags: Small Molecule Therapeutics Source Type: research
Folate-Hapten-Mediated Immunotherapy Synergizes with Vascular Endothelial Growth Factor Receptor Inhibitors in Treating Murine Models of Cancer
We report that sunitinib and axitinib (VEGF receptor inhibitors that simultaneously mitigate immune suppression) synergize with the folate-hapten–targeted immunotherapy to reduce tumor growth in three different syngeneic murine tumor models. We further demonstrate that the combination therapy not only enhances tumor infiltration of CD4+ and CD8+ effector cells, but surprisingly reduces tumor neovasculogenesis more than predicted. Subsequent investigation of the mechanism for this unexpected suppression of neovasculogenesis revealed that it is independent of elimination of any tumor cells, but instead likely derives f...
Source: Molecular Cancer Therapeutics - March 1, 2017 Category: Cancer & Oncology Authors: Bandara, N. A., Bates, C. D., Lu, Y., Hoylman, E. K., Low, P. S. Tags: Small Molecule Therapeutics Source Type: research
Evaluation of Nonpeptidic Ligand Conjugates for the Treatment of Hypoxic and Carbonic Anhydrase IX-Expressing Cancers
The majority of tumors contain regions of hypoxia, which cause marked phenotypic changes to resident cells. This altered gene expression often leads to increased resistance to anticancer treatments. Therefore, elimination of these resistant hypoxic cells is crucial to prevent disease recurrence. Herein, we describe the selective delivery of imaging and chemotherapeutic agents to cells expressing carbonic anhydrase IX (CA IX), a highly upregulated hypoxia receptor. These agents were conjugated to a potent divalent CA IX ligand through a hydrophilic PEG linker. These conjugates are shown to bind CA IX–expressing cells ...
Source: Molecular Cancer Therapeutics - March 1, 2017 Category: Cancer & Oncology Authors: Lv, P.-C., Roy, J., Putt, K. S., Low, P. S. Tags: Small Molecule Therapeutics Source Type: research
Nanoparticle-Based Celecoxib and Plumbagin for the Synergistic Treatment of Melanoma
This study details the development of a nanoliposomal-based agent containing celecoxib and plumbagin, called CelePlum-777, which is stable and releases these drugs at an optimal ratio for maximal synergistic killing efficacy. CelePlum-777 was more effective at killing melanoma than normal cells and inhibited xenograft melanoma tumor growth by up to 72% without apparent toxicity. Mechanistically, the drug combination in CelePlum-777 led to enhanced inhibition of melanoma cell proliferation mediated by decreasing levels of key cyclins important for cancer cell proliferation and survival, which was not observed with the indiv...
Source: Molecular Cancer Therapeutics - March 1, 2017 Category: Cancer & Oncology Authors: Gowda, R., Kardos, G., Sharma, A., Singh, S., Robertson, G. P. Tags: Small Molecule Therapeutics Source Type: research
Clinical Dosing Regimen of Selinexor Maintains Normal Immune Homeostasis and T-cell Effector Function in Mice: Implications for Combination with Immunotherapy
Selinexor (KPT-330) is a first-in-class nuclear transport inhibitor currently in clinical trials as an anticancer agent. To determine how selinexor might affect antitumor immunity, we analyzed immune homeostasis in mice treated with selinexor and found disruptions in T-cell development, a progressive loss of CD8 T cells, and increases in inflammatory monocytes. Antibody production in response to immunization was mostly normal. Precursor populations in bone marrow and thymus were unaffected by selinexor, suggesting that normal immune homeostasis could recover. We found that a high dose of selinexor given once per week prese...
Source: Molecular Cancer Therapeutics - March 1, 2017 Category: Cancer & Oncology Authors: Tyler, P. M., Servos, M. M., de Vries, R. C., Klebanov, B., Kashyap, T., Sacham, S., Landesman, Y., Dougan, M., Dougan, S. K. Tags: Small Molecule Therapeutics Source Type: research
The Exportin-1 Inhibitor Selinexor Exerts Superior Antitumor Activity when Combined with T-Cell Checkpoint Inhibitors
Selinexor, a selective inhibitor of nuclear export (SINE) compound targeting exportin-1, has previously been shown to inhibit melanoma cell growth in vivo. We hypothesized that combining selinexor with antibodies that block or disrupt T-cell checkpoint molecule signaling would exert superior antimelanoma activity. In vitro, selinexor increased PDCD1 and CTLA4 gene expression in leukocytes and induced CD274 gene expression in human melanoma cell lines. Mice bearing syngeneic B16F10 melanoma tumors demonstrated a significant reduction in tumor growth rate in response to the combination of selinexor and anti-PD-1 or anti-PD-L...
Source: Molecular Cancer Therapeutics - March 1, 2017 Category: Cancer & Oncology Authors: Farren, M. R., Hennessey, R. C., Shakya, R., Elnaggar, O., Young, G., Kendra, K., Landesman, Y., Elloul, S., Crochiere, M., Klebanov, B., Kashyap, T., Burd, C. E., Lesinski, G. B. Tags: Small Molecule Therapeutics Source Type: research
Highlights of This Issue
(Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - March 1, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research
Near Infrared Photoimmunotherapy in a Transgenic Mouse Model of Spontaneous Epidermal Growth Factor Receptor (EGFR)-expressing Lung Cancer
In conclusion, NIR-PIT effectively treated a spontaneous lung cancer in a hEGFR-TL transgenic mouse model. MRI successfully monitored the therapeutic effects of NIR-PIT. Mol Cancer Ther; 16(2); 408–14. ©2016 AACR. (Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - February 1, 2017 Category: Cancer & Oncology Authors: Nakamura, Y., Ohler, Z. W., Householder, D., Nagaya, T., Sato, K., Okuyama, S., Ogata, F., Daar, D., Hoa, T., Choyke, P. L., Kobayashi, H. Tags: Models and Technologies Source Type: research
Repositioning FDA-Approved Drugs in Combination with Epigenetic Drugs to Reprogram Colon Cancer Epigenome
Epigenetic drugs, such as DNA methylation inhibitors (DNMTi) or histone deacetylase inhibitors (HDACi), are approved in monotherapy for cancer treatment. These drugs reprogram gene expression profiles, reactivate tumor suppressor genes (TSG) producing cancer cell differentiation and apoptosis. Epigenetic drugs have been shown to synergize with other epigenetic drugs or various anticancer drugs. To discover new molecular entities that enhance epigenetic therapy, we performed a high-throughput screening using FDA-approved libraries in combination with DNMTi or HDACi. As a screening model, we used YB5 system, a human colon ca...
Source: Molecular Cancer Therapeutics - February 1, 2017 Category: Cancer & Oncology Authors: Raynal, N. J.- M., Da Costa, E. M., Lee, J. T., Gharibyan, V., Ahmed, S., Zhang, H., Sato, T., Malouf, G. G., Issa, J.-P. J. Tags: Models and Technologies Source Type: research
HEXIM1 as a Robust Pharmacodynamic Marker for Monitoring Target Engagement of BET Family Bromodomain Inhibitors in Tumors and Surrogate Tissues
An increasing number of BET family protein inhibitors have recently entered clinical trials. It has been reported that attempts of monitoring target engagement of the BET bromodomain inhibitor OTX015 using literature-described putative pharmacodynamic markers, such as c-Myc, BRD2, etc., failed to detect pharmacodynamic marker responses in AML patients treated at active dose and those with clinical responses. Here, we report the identification and characterization of HEXIM1 and other genes as robust pharmacodynamic markers for BET inhibitors. Global gene expression profiling studies were carried out using cancer cells and s...
Source: Molecular Cancer Therapeutics - February 1, 2017 Category: Cancer & Oncology Authors: Lin, X., Huang, X., Uziel, T., Hessler, P., Albert, D. H., Roberts-Rapp, L. A., McDaniel, K. F., Kati, W. M., Shen, Y. Tags: Companion Diagnostics and Cancer Biomarkers Source Type: research
Microdose-Induced Drug-DNA Adducts as Biomarkers of Chemotherapy Resistance in Humans and Mice
We report progress on predicting tumor response to platinum-based chemotherapy with a novel mass spectrometry approach. Fourteen bladder cancer patients were administered one diagnostic microdose each of [14C]carboplatin (1% of the therapeutic dose). Carboplatin–DNA adducts were quantified by accelerator mass spectrometry in blood and tumor samples collected within 24 hours, and compared with subsequent chemotherapy response. Patients with the highest adduct levels were responders, but not all responders had high adduct levels. Four patient-derived bladder cancer xenograft mouse models were used to test the possibili...
Source: Molecular Cancer Therapeutics - February 1, 2017 Category: Cancer & Oncology Authors: Zimmermann, M., Wang, S.-S., Zhang, H., Lin, T.-y., Malfatti, M., Haack, K., Ognibene, T., Yang, H., Airhart, S., Turteltaub, K. W., Cimino, G. D., Tepper, C. G., Drakaki, A., Chamie, K., de Vere White, R., Pan, C.-x., Henderson, P. T. Tags: Companion Diagnostics and Cancer Biomarkers Source Type: research
Imatinib Spares cKit-Expressing Prostate Neuroendocrine Tumors, whereas Kills Seminal Vesicle Epithelial-Stromal Tumors by Targeting PDGFR-{beta}
Prostate cancer is a leading cause of cancer-related death in males worldwide. Indeed, advanced and metastatic disease characterized by androgen resistance and often associated with neuroendocrine (NE) differentiation remains incurable. Using the spontaneous prostate cancer TRAMP model, we have shown that mast cells (MCs) support in vivo the growth of prostate adenocarcinoma, whereas their genetic or pharmacologic targeting favors prostate NE cancer arousal. Aiming at simultaneously targeting prostate NE tumor cells and MCs, both expressing the cKit tyrosine kinase receptor, we have tested the therapeutic effect of imatini...
Source: Molecular Cancer Therapeutics - February 1, 2017 Category: Cancer & Oncology Authors: Jachetti, E., Rigoni, A., Bongiovanni, L., Arioli, I., Botti, L., Parenza, M., Cancila, V., Chiodoni, C., Festinese, F., Bellone, M., Tardanico, R., Tripodo, C., Colombo, M. P. Tags: Cancer Biology and Signal Transduction Source Type: research
