Vessel-Targeted Chemophototherapy with Cationic Porphyrin-Phospholipid Liposomes
Cationic liposomes have been used for targeted drug delivery to tumor blood vessels, via mechanisms that are not fully elucidated. Doxorubicin (Dox)-loaded liposomes were prepared that incorporate a cationic lipid; 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP), along with a small amount of porphyrin-phospholipid (PoP). Near-infrared (NIR) light caused release of entrapped Dox via PoP-mediated DOTAP photo-oxidation. The formulation was optimized to enable extremely rapid NIR light-triggered Dox release (i.e., in 15 seconds), while retaining reasonable serum stability. In vitro, cationic PoP liposomes readily bound to bot...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Luo, D., Geng, J., Li, N., Carter, K. A., Shao, S., Atilla-Gokcumen, G. E., Lovell, J. F. Tags: Large Molecule Therapeutics Source Type: research
Potency-matched Dual Cytokine-Antibody Fusion Proteins for Cancer Therapy
A novel biopharmaceutical, consisting of the F8 mAb (specific to a splice isoform of fibronectin) simultaneously fused to both TNF and IL2, was found to react with the majority of solid tumors and hematologic malignancies in mouse and man, but not with healthy adult tissues. The product selectively localized to neoplastic lesions in vivo, as evidenced by quantitative biodistribution studies using radioiodinated protein preparations. When the potency of the cytokine payloads was matched by a single-point mutation, the resulting fusion protein (IL2-F8-TNFmut) eradicated soft-tissue sarcomas in immunocompetent mice, which did...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Luca, R. D., Soltermann, A., Pretto, F., Pemberton-Ross, C., Pellegrini, G., Wulhfard, S., Neri, D. Tags: Large Molecule Therapeutics Source Type: research
mTOR Kinase Inhibition Effectively Decreases Progression of a Subset of Neuroendocrine Tumors that Progress on Rapalog Therapy and Delays Cardiac Impairment
In conclusion, in the majority of pNETs that progress on rapalogs, it is possible to reduce disease progression using an mTORKi, such as CC-223. Moreover, CC-223 had an additional transient cardiac benefit on valvular fibrosis compared with placebo- or rapalog-treated mice. These results provide the preclinical rationale to further develop mTORKi clinically upon progression on rapalog therapy and to further test their long-term cardioprotective benefit in those NET patients prone to carcinoid syndrome. Mol Cancer Ther; 16(11); 2432–41. ©2017 AACR. (Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Orr-Asman, M. A., Chu, Z., Jiang, M., Worley, M., LaSance, K., Koch, S. E., Carreira, V. S., Dahche, H. M., Plas, D. R., Komurov, K., Qi, X., Mercer, C. A., Anthony, L. B., Rubinstein, J., Thomas, H. E. Tags: Small Molecule Therapeutics Source Type: research
Targeting Phosphatidylinositol 3-Kinase Signaling Pathway for Therapeutic Enhancement of Vascular-Targeted Photodynamic Therapy
Vascular-targeted photodynamic therapy (PDT) selectively disrupts vascular function by inducing oxidative damages to the vasculature, particularly endothelial cells. Although effective tumor eradication and excellent safety profile are well demonstrated in both preclinical and clinical studies, incomplete vascular shutdown and angiogenesis are known to cause tumor recurrence after vascular-targeted PDT. We have explored therapeutic enhancement of vascular-targeted PDT with PI3K signaling pathway inhibitors because the activation of PI3K pathway was involved in promoting endothelial cell survival and proliferation after PDT...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Kraus, D., Palasuberniam, P., Chen, B. Tags: Small Molecule Therapeutics Source Type: research
Targeting TAO Kinases Using a New Inhibitor Compound Delays Mitosis and Induces Mitotic Cell Death in Centrosome Amplified Breast Cancer Cells
Thousand-and-one amino acid kinases (TAOK) 1 and 2 are activated catalytically during mitosis and can contribute to mitotic cell rounding and spindle positioning. Here, we characterize a compound that inhibits TAOK1 and TAOK2 activity with IC50 values of 11 to 15 nmol/L, is ATP-competitive, and targets these kinases selectively. TAOK inhibition or depletion in centrosome-amplified SKBR3 or BT549 breast cancer cell models increases the mitotic population, the percentages of mitotic cells displaying amplified centrosomes and multipolar spindles, induces cell death, and inhibits cell growth. In contrast, nontumorigenic and di...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Koo, C.-Y., Giacomini, C., Reyes-Corral, M., Olmos, Y., Tavares, I. A., Marson, C. M., Linardopoulos, S., Tutt, A. N., Morris, J. D. H. Tags: Small Molecule Therapeutics Source Type: research
Dual Inhibition of Hedgehog and c-Met Pathways for Pancreatic Cancer Treatment
In this study, utilizing mouse models of PDAC, we showed that inhibition of either HGF/c-Met or Hh pathways sensitize the PDAC tumors to gemcitabine, resulting in decreased primary tumor volume as well as significant reduction of metastatic tumor burden. However, prolonged treatment of single HGF/c-Met or Hh inhibitor leads to resistance to these single inhibitors, likely because the single c-Met treatment leads to enhanced expression of Shh, and vice versa. Targeting both the HGF/c-Met and Hh pathways simultaneously overcame the resistance to the single-inhibitor treatment and led to a more potent antitumor effect in comb...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Rucki, A. A., Xiao, Q., Muth, S., Chen, J., Che, X., Kleponis, J., Sharma, R., Anders, R. A., Jaffee, E. M., Zheng, L. Tags: Small Molecule Therapeutics Source Type: research
Combination Therapy with c-Met and Src Inhibitors Induces Caspase-Dependent Apoptosis of Merlin-Deficient Schwann Cells and Suppresses Growth of Schwannoma Cells
This study demonstrates that simultaneous inhibition of c-Met and Src signaling in MD-MSCs triggers apoptosis and reveals vulnerable pathways that could be exploited to develop NF2 therapies. Mol Cancer Ther; 16(11); 2387–98. ©2017 AACR. (Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Fuse, M. A., Plati, S. K., Burns, S. S., Dinh, C. T., Bracho, O., Yan, D., Mittal, R., Shen, R., Soulakova, J. N., Copik, A. J., Liu, X. Z., Telischi, F. F., Chang, L.-S., Franco, M. C., Fernandez-Valle, C. Tags: Small Molecule Therapeutics Source Type: research
The p97 Inhibitor CB-5083 Is a Unique Disrupter of Protein Homeostasis in Models of Multiple Myeloma
Inhibition of the AAA ATPase, p97, was recently shown to be a novel method for targeting the ubiquitin proteasome system, and CB-5083, a first-in-class inhibitor of p97, has demonstrated broad antitumor activity in a range of both hematologic and solid tumor models. Here, we show that CB-5083 has robust activity against multiple myeloma cell lines and a number of in vivo multiple myeloma models. Treatment with CB-5083 is associated with accumulation of ubiquitinated proteins, induction of the unfolded protein response, and apoptosis. CB-5083 decreases viability in multiple myeloma cell lines and patient-derived multiple my...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Moigne, R. L., Aftab, B. T., Djakovic, S., Dhimolea, E., Valle, E., Murnane, M., King, E. M., Soriano, F., Menon, M.-K., Wu, Z. Y., Wong, S. T., Lee, G. J., Yao, B., Wiita, A. P., Lam, C., Rice, J., Wang, J., Chesi, M., Bergsagel, P. L., Kraus, M., Driess Tags: Small Molecule Therapeutics Source Type: research
Animacroxam, a Novel Dual-Mode Compound Targeting Histone Deacetylases and Cytoskeletal Integrity of Testicular Germ Cell Cancer Cells
Novel approaches for the medical treatment of advanced solid tumors, including testicular germ cell tumors (TGCT), are desperately needed. Especially, TGCT patients not responding to cisplatin-based therapy need therapeutic alternatives, as there is no effective medical treatment available for this particular subgroup. Here, we studied the suitability of the novel dual-mode compound animacroxam for TGCT treatment. Animacroxam consists of an HDAC-inhibitory hydroxamate moiety coupled to a 4,5-diarylimidazole with inherent cytoskeleton disrupting potency. Animacroxam revealed pronounced antiproliferative, cell-cycle arrestin...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Steinemann, G., Dittmer, A., Kuzyniak, W., Hoffmann, B., Schrader, M., Schobert, R., Biersack, B., Nitzsche, B., Höpfner, M. Tags: Small Molecule Therapeutics Source Type: research
Targeting the MAPK Signaling Pathway in Cancer: Promising Preclinical Activity with the Novel Selective ERK1/2 Inhibitor BVD-523 (Ulixertinib)
Aberrant activation of signaling through the RAS–RAF–MEK–ERK (MAPK) pathway is implicated in numerous cancers, making it an attractive therapeutic target. Although BRAF and MEK-targeted combination therapy has demonstrated significant benefit beyond single-agent options, the majority of patients develop resistance and disease progression after approximately 12 months. Reactivation of ERK signaling is a common driver of resistance in this setting. Here we report the discovery of BVD-523 (ulixertinib), a novel, reversible, ATP-competitive ERK1/2 inhibitor with high potency and ERK1/2 selectivity. In vitro B...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Germann, U. A., Furey, B. F., Markland, W., Hoover, R. R., Aronov, A. M., Roix, J. J., Hale, M., Boucher, D. M., Sorrell, D. A., Martinez-Botella, G., Fitzgibbon, M., Shapiro, P., Wick, M. J., Samadani, R., Meshaw, K., Groover, A., DeCrescenzo, G., Namchu Tags: Small Molecule Therapeutics Source Type: research
A Bifunctional MAPK/PI3K Antagonist for Inhibition of Tumor Growth and Metastasis
Responses to targeted therapies frequently are brief, with patients relapsing with drug-resistant tumors. For oncogenic MEK and BRAF inhibition, drug resistance commonly occurs through activation of PI3K/AKT/mTOR signaling and immune checkpoint modulation, providing a robust molecular target for concomitant therapy. Here, we evaluated the efficacy of a bifunctional kinase inhibitor (ST-162) that concurrently targets MAPK and PI3K signaling pathways. Treatment with ST-162 produced regression of mutant KRAS- or BRAF-addicted xenograft models of colorectal cancer and melanoma and stasis of BRAF/PTEN–mutant melanomas. Co...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Galban, S., Apfelbaum, A. A., Espinoza, C., Heist, K., Haley, H., Bedi, K., Ljungman, M., Galban, C. J., Luker, G. D., Dort, M. V., Ross, B. D. Tags: Small Molecule Therapeutics Source Type: research
Inhibition of the V-ATPase by Archazolid A: A New Strategy to Inhibit EMT
Epithelial–mesenchymal transition (EMT) induces tumor-initiating cells (TIC), which account for tumor recurrence, metastasis, and therapeutic resistance. Strategies to interfere with EMT are rare but urgently needed to improve cancer therapy. By using the myxobacterial natural compound Archazolid A as a tool, we elucidate the V-ATPase, a multimeric proton pump that regulates lysosomal acidification, as a crucial player in EMT and identify the inhibition of V-ATPase by Archazolid A as a promising strategy to block EMT. Genetic knockdown and pharmacologic inhibition of the V-ATPase by Archazolid A interfere with the EM...
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Authors: Merk, H., Messer, P., Ardelt, M. A., Lamb, D. C., Zahler, S., Müller, R., Vollmar, A. M., Pachmayr, J. Tags: Small Molecule Therapeutics Source Type: research
Highlights of This Issue
(Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - November 1, 2017 Category: Cancer & Oncology Tags: Highlights Source Type: research
Retraction: EGFR-Mediated Reactivation of MAPK Signaling Induces Acquired Resistance to GSK2118436 in BRAF V600E-Mutant NSCLC Cell Lines
(Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Tags: Retraction Source Type: research
Wnt Signaling Inhibition Promotes Apoptosis in Sarcomas--Response
(Source: Molecular Cancer Therapeutics)
Source: Molecular Cancer Therapeutics - October 2, 2017 Category: Cancer & Oncology Authors: Martinez-Font, E., Vögler, O., Alemany, R., Obrador-Hevia, A. Tags: Letter to the Editor Source Type: research
