Sacituzumab govitecan is an antibody-drug conjugate. It is composed of a humanized monoclonal antibody raised against the trophoblast cell-surface antigen 2 (Trop-2), and linked to SN-38, which is an active metabolite of topoisomerase I inhibitor anticancer drug irinotecan. A hydrolyzable linker conjugates the antibody and the drug. Trop-2 is overexpressed in various tumors including the triple-negative breast cancers (TNBCs) that are more aggressive with limited therapeutic options. Sacituzumab govitecan has proven to be an important therapeutic modality to manage the TNBCs. It has shown progression-free survival (PFS) and overall survival (OS) benefits when compared to standard-of-care chemotherapeutics. Accordingly, it is approved for the treatment of TNBCs in the United States and the European Union. Sacituzumab govitecan has also shown PFS and OS benefits for hormone receptor-positive (HR+) and human epidermal growth factor receptor-2-negative (HER2-) metastatic breast cancers. Therefore, sacituzumab govitecan appears to be an option for HR+/HER2- metastatic breast cancers that are heavily pretreated and exhibit endocrine resistance. Although sacituzumab govitecan has shown promise, it also is toxic. Additional studies are therefore needed to further refine the use of sacituzumab govitecan in improving the management of metastatic breast cancer.
The cyclin-dependent kinase (CDK) inhibitors have emerged as important cancer therapeutics. To date, three CDK4/6 inhibitors in combination with endocrine therapy have been approved by the U.S. Food and Drug Administration for the treatment of hormone receptor-positive, HER2-negative advanced breast cancer. These include, palbociclib, ribociclib and abemaciclib. More recently, a newer CDK4/6 inhibitor named dalpiciclib has been tested in the phase III DAWNA-1 study, which is a randomized, double-blind, placebo-controlled trial that investigates dalpiciclib in combination with fulvestrant in hormone receptor-positive, HER2-negative advanced breast cancer patients that have relapsed or progressed on prior endocrine therapy. Dalpiciclib is an oral agent and an emerging ATP-competitive CDK4/6 inhibitor. The interim results of DAWNA-1 study revealed that dalpiciclib in combination with fulvestrant significantly prolonged the progression-free survival. The clinical use and side effects of palbociclib, ribociclib and abemaciclib as well as dalpiciclib are reviewed here.
800x600 Pembrolizumab is an immune checkpoint inhibitor antibody. It is a humanized monoclonal antibody directed against cytotoxic T cell immune checkpoint receptor named programmed death 1 (PD-1) (1, 2). PD1 is believed to transduce inhibitory signals when bound to its ligand PD-L1 or PD-L2 (1, 2). Pembrolizumab when bound to PD1 is believed to block PD1 interactions with PD-L1/PD-L2 and consequently enhances cytotoxic T cell effects on tumor cells (1, 2). In a recent article, Normal 0 false false false EN-US X-NONE X-NONE MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman","serif";}
Protein kinase D (PKD) belongs to a family of serine/threonine kinases in the calcium/calmodulin-dependent kinase superfamily. It modulates a number of signal transduction pathways involved in regulation of cell proliferation, survival, migration, angiogenesis, regulation of gene expression, and protein/membrane trafficking, mediated by variety of stimuli such as growth factors, hormones, and cellular stresses. Although its role in cancer progression remains elusive, current literature supports a potential tumor promoting function of the selective PKD isoforms in prostate cancer, making them promising therapeutic targets for cancer treatment.
Anaplastic lymphoma kinase (ALK) gene is present on chromosome 2. ALK gene locus undergoes inversion leading to echinoderm microtubule-associated protein-like 4 (EML4) gene and ALK gene fusion resulting in an oncogenic fusion protein. The ALK abnormality occurs in ~3-7% of non-small cell lung carcinoma (NSCLC) and generally associates with adenocarcinoma in those who never smoked or smoked occasionally. Crizotinib (Xalkori) was the first ALK inhibitor approved by the FDA in 2013 for the treatment of ALK-positive NSCLC patients. However, resistance is noted within about one year of treatment with crizotinib....
In this issue, Molecular and Cellular Pharmacology profiles Jie An, Ph.D. and her expertise in the fields of pharmacogenomics and personalized medicine. Dr. An is the Assistant Director and Principal Scientist in the Laboratory of Gulfstream Genomics at Gulfstream Diagnostics, Dallas, Texas, USA. Dr. An is an expert in the fields of pharmacogenomics and personalized medicine. She is a founding member of Gulfstream Genomics and devotes her efforts to study the influences of genetic variability on drug response. Dr. An also provides scientific leadership in technical development and clinical implementation of pharmacogenetic testing. Pharmacogenomics and personalized medicine are emerging areas with a limited number of experts. Therefore, Dr. An is among a select few experts of these disciplines. Molecular and Cellular Pharmacology presents her views on the progress of these disciplines in a ‘Question and Answer’ format.
800x600 Nivolumab, a human IgG4 monoclonal antibody against the T cell receptor programmed death 1 (PD-1), is an immune checkpoint inhibitor (1, 2). It has shown significant therapeutic promise as an anticancer agent for various malignancies. A recent study has reported the outcome of a phase 3 trial that.... Normal 0 false false false EN-US X-NONE X-NONE MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:"Table Normal"; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:""; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:"Times New Roman","serif";}
Mechanistic target of rapamycin (mTOR) is a conserved threonine and serine protein kinase that was identified more than two decades ago as the target of immunosuppressive drug rapamycin. Since then considerable amount of information has been learned about the function of this kinase. It is now well-established that mTOR plays a pivotal role in governing cell growth and proliferation, hence making mTOR a therapeutic target for disease conditions caused by deregulated cell proliferation, such as cancer. In the past decade, numerous mTOR inhibitors have been developed and many are currently in clinical trials for cancer treatment. This commentary is to provide a brief summary of these mTOR inhibitors.
800x600 Carisoprodol is a centrally-acting skeletal muscle relaxant frequently prescribed for acute musculoskeletal conditions. Recreational use of carisoprodol is an increasing problem. Tolerance to carisoprodol develops quickly and abusers often take 10-20 times the normal dose, leading to intoxicating effects. Also, abrupt cessation of carisoprodol results in severe withdrawal syndrome including delusions, seizures and even death. Considering its alarming rate of abuse and subsequent consequences, carisoprodol was scheduled (schedule IV) at the federal level effective January 11, 2012 . Until recently, it was widely accepted that the sedative and muscle relaxant effects of carisoprodol were due predominantly to its metabolite, meprobamate. However, it is now clear that carisoprodol itself modulates and directly gates γ-aminobutyric acid type A receptors (GABA A Rs), the predominant inhibitory neurotransmitter receptors in mammalian brain. Recent work has provided additional insight into carisoprodol’s interaction with GABA A Rs. This may underlie the ability of carisoprodol in enhancing the sedative effects of CNS depressants, contributing to its potential for abuse. In this review, we discuss current understanding with regard to the abuse potential of carisoprodol, therapeutic and abuse-related actions of this drug, and possible molecular actions that underlie these effects. Normal 0 false false false EN-US X-NONE X-NONE MicrosoftInternetExplorer4 /* Style Definitions */ table.MsoNormalTable {mso-style-name:Table Normal; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:10.0pt; font-family:Times New Roman,serif;}
Genotoxic chemotherapeutics particularly cisplatin remain effective for clinical management of various malignancies including lung cancer. However, the development of chemoresistance leads to treatment failure. The mechanisms by which tumor cells acquire resistance to chemotherapy are multifaceted in nature and some remain to be fully elucidated. Recently, a potential role of RNA-binding protein hnRNPA0 in chemoresistance of p53-defective lung cancer cells was reported. Genotoxic (DNA damaging) chemotherapy was reported to activate hnRNPA0 which in turn post-transcriptionally regulated p27Kip1 and Gadd45-alpha by stabilizing their mRNAs. Regulation of p27Kip1 and Gadd45-alpha led to enforcement of G1/S and G2/M checkpoints thereby providing time for DNA repair and thus, resistance to chemotherapy. The identification of a signaling network involving the kinase MK2, hnRNPA0, p27Kip1 and Gadd45-alpha that may predict response to chemotherapy is an interesting finding. Further studies are now needed to gain additional insights as to whether this network is restricted only to a subset of tumors or more broadly relevant across multiple tumor types.
Nanoscale drug delivery systems represent an attractive strategy to improve both the efficacy and safety of anticancer drugs. In this work, we describe nanoformulation of curcumin, a most potent natural anticancer compound capable of killing cancer cells while sparing the normal tissues. Since curcumin is a natural hydrophobic polyphenol, it has a low aqueous solubility and bioavailability, which are challenging to its therapeutic efficacy. We developed and evaluated a novel colloidal nanogel carrier for encapsulation of curcumin to increase its solubility and cytotoxicity. Amphiphilic Poloxamer-cationic network in the nanogel NG127 was designed to efficiently encapsulate curcumin. Homogenous drug complexes were obtained with 20-25% content of curcumin and the particle size of ca. 150 nm. Using ImageStream multispectral imaging flow cytometry, we demonstrated that the curcumin-nanogel formulation (C-NG) was readily internalized into MDA-231 breast cancer cells. A real-time cell growth electronic sensing assay was used to measure proliferation responses of various breast cancer cells to C-NG treatments. Our results indicated that the C-NG formulation was 70-85% more effective in inhibiting growth, at concentrations lower than IC50 of free curcumin. This was also confirmed morphologically by modified acridine orange/ethidium bromide staining and fluorescent microscopy. Importantly, nanocarrier NG127 alone displayed practically no cytotoxicity. We conclude that nanogel carriers offer an innovative way to encapsulate curcumin and to obtain more effective anticancer therapeutics than curcumin alone with a potential to specific tumor targeting, such as using antibodies against surface receptors specific to breast cancer cells.
CK2 is a master regulator protein kinase which demonstrates heightened expression in diverse cancer types and is considered a promising target for therapy. Given its ubiquitous expression and potent influence on cell survival, cancer cell-directed targeting of the CK2 signal is an important factor for development of an anti-CK2 therapeutic. We previously reported on the malignant cell specificity and effect on CK2 signaling of a tenfibgen (TBG) based nanocapsule for delivery of the CK2 small molecule inhibitor 2-dimethylamino-4,5,6,7-tetrabromo-1H-benzimidazole (DMAT) in cultured prostate cancer cells. Here we tested the ability of TBG-DMAT to affect the growth of prostate xenograft tumors in mice. Our results show that treatment of PC3-LN4 xenograft tumors with TBG-DMAT caused loss of proliferative Ki-67 signal as well as Nuclear Factor-kappa B (NF-κB) expression in the tumors. Further, the TBG-DMAT nanocapsule was detected in tumors and not in liver or testis. In conclusion, TBG-based nanocapsule delivery of anti-CK2 small molecule drugs holds significant promise for treatment of prostate cancer.
Lipids are important cellular building blocks and components of signaling cascades. Deregulation of lipid metabolism or signaling is frequently linked to a variety of human diseases such as diabetes, cardiovascular diseases, and cancer. It is widely believed that lipid molecules or their metabolic products are involved in tumorigenic inflammation and thus, lipids are implicated as significant contributors or even primary triggers of tumorigenesis. Lipids are believed to directly or indirectly activate growth promoting signals such as those involving LPA, insulin, IGF-1 and EGF to promote cancer cell growth. Cellular levels of certain lipids, including sphingosine-1-phosphate and ceramide, maintain a delicate balance between cell death and survival and alterations in their levels lead to unfavorable consequences including tumorigenesis. This article provides an overview of current knowledge that implicates lipids in tumorigenesis and explores the potential mechanisms that support a positive link between obesity and cancer.
Malignant melanoma remains one of the fastest growing cancers worldwide. Although the primary cutaneous melanoma can be managed by surgery, the advanced metastatic melanoma cannot be managed by surgery alone and thus, requires better therapeutic approaches. In view of high mortality rates due to metastatic melanoma, better understanding of the molecular pathogenesis of malignant melanoma is urgently needed. Such information is expected to prove very valuable in early detection of potential metastatic lesions and developing newer therapeutic approaches in order to better manage this malignancy. This article reviews the available information on the molecular changes associated with malignant melanoma and discusses the potential of such information in facilitating the development of newer anti-melanoma therapeutics. Current state of knowledge and the future of traditional and newly approved anti-melanoma therapeutics are also discussed.
800x600 In quest of novel selective JNK-1 inhibitors targeted towards type II diabetes, ligand and structure based pharmacophore generation approach were employed. In ligand based approach, a dataset of 40 inhibitors was selected as training set. The best hypothesis with one H-bond acceptor, two H-bond donor and one hydrophobic feature was selected on the basis of correlation coefficient, RMSD and cost difference of 0.89, 0.89 and 49.73, respectively. The reliability of Hypo 1 was established using three different methods, namely, cost analysis, test set prediction and cat scramble. All three methods confirmed the predictive power and robustness of the developed hypothesis. In addition to ligand based, a structure-based pharmacophore generation approach was also employed to discover novel structural characteristics for JNK-1 inhibitors. Like ligand-based approach, the structure-based hypothesis suggests the significance of hydrogen bond donors, hydrogen bond acceptors and hydrophobic groups involved in the inhibitor-JNK-1 receptor interaction. The validated pharmacophore model was then used for searching new lead compounds from NCI database. Three compounds (NSC687937, NSC210378 and NSC120934) were retrieved as structurally diverse druggable novel leads.
Lymphoma is rising in incidence and there is a continued need for new and novel therapeutic options. Lymphomas are extremely radiosensitive, but the majority of patients are not candidates for involved field radiation therapy. An intact immune system has a critical role in suppressing lymphomagenesis. Here we discuss the contribution of various components of the immune system in suppressing the development of lymphoma, as elucidated from mouse models. We review the nature of the immune response to lymphoma in non-immunocompromised patients. Finally, we discuss the potential role of immunomodulation, in concert with radiation therapy, as a component of future therapeutic strategies for lymphoma.
Mitochondrial morphology and metabolism play an important role in cellular homeostasis. Recent studies have shown that the fidelity of mitochondrial morphology is important in maintaining mitochondrial shape, number, size, membrane potential, ATP synthesis, mtDNA, motility, signaling, quality control, response to cellular stress, mitophagy and apoptosis. This article provides an overview of the current state of knowledge of the fission and fusion machinery with a focus on the mechanisms underlying the regulation of the mitochondrial morphology and cellular energy state. Several lines of evidence indicate that dysregulation of mitochondrial fission or fusion is associated with mitochondrial dysfunction, which in turn impacts mitophagy and apoptosis. Metabolic disorders are also associated with dysregulation of fission or fusion and the available lines of evidence point to a bidirectional interplay between the mitochondrial fission or fusion reactions and bioenergetics. Clearly, more in-depth studies are needed to fully elucidate the mechanisms that control mitochondrial fission and fusion. It is envisioned that the outcome of such studies will improve the understanding of the molecular basis of related metabolic disorders and also facilitate the development of better therapeutics.
Stereotactic ablative radiotherapy (SABR) has been demonstrated to provide excellent local control in several malignancies. Recent reports have suggested that this ablative dose may impact disease outside of the radiated area. Furthermore, these studies have implicated immune modulation as the primary mechanism of disease response outside the irradiated area. More specifically, T-cell stimulation and tumor necrosis factor-α modulation following high dose irradiation have been suggested as the responsible components of this phenomenon. In addition, the "abscopal effect" may play a role in disease response outside of the radiated area. We review the current literature regarding the effects of ablative radiation therapy, the potential for immune modulation from it, and the mechanisms of the distant effects it elicits.
Sh Faisal 14.00 Magnetic resonance imaging (MRI) offers the possibility to accurately detect, localize, and stage prostate cancer, thereby assisting in the selection of an individualized course of treatment. Conventional, anatomical MRI (T2-weighted MRI) lacks the required sensitivity and specificity, in identifying prostate cancer foci, especially in the transition zone, in areas of post-biopsy hemorrhage, and in the setting of post-treatment change. In addition, T2-weighted MRI is suboptimal in determining the presence of extracapsular extension (ECE), which can be the most important factor for selection of an individualized therapy and for predicting the risk of tumor recurrence. Advanced MRI techniques comprising of dynamic contrast enhanced -MRI (DCE-MRI) that provides vascular information, diffusion-weighted MRI (DWI) that provides biophysical information, and magnetic resonance spectroscopic imaging (MRSI) that provides metabolic information can assist in overcoming the limitations of conventional anatomical MRI. In this article, we provide a brief review of these advanced imaging techniques and how they correlate with pathologic findings in prostate cancer. Advanced MRI techniques may increase the specificity of conventional MRI by identifying functional, metabolic, and microstructural changes of the prostate that occur in areas of cancer. MRSI and DWI have added value in detecting tumor within the transitional zone of the prostate, while MRSI and DCE may assist in predicting the presence of ECE, as well as in evaluating for recurrent tumor following hormonal or radiation therapy. Using a combined multi-parametric approach can provide a thorough evaluation for the presence and extent of prostate cancer using MRI. Normal 0 false false false EN-US X-NONE X-NONE /* Style Definitions */ table.MsoNormalTable {mso-style-name:Table Normal; mso-tstyle-rowband-size:0; mso-tstyle-colband-size:0; mso-style-noshow:yes; mso-style-priority:99; mso-style-parent:; mso-padding-alt:0in 5.4pt 0in 5.4pt; mso-para-margin:0in; mso-para-margin-bottom:.0001pt; mso-pagination:widow-orphan; font-size:12.0pt; font-family:Calibri,sans-serif; mso-ascii-font-family:Calibri; mso-ascii-theme-font:minor-latin; mso-hansi-font-family:Calibri; mso-hansi-theme-font:minor-latin;}
This review was conceived with the aim of presenting a comprehensive account of the molecular interactions of artemisinin class of antimalarials and delineating it in the context of the different theoretical models of artemisinin mechanism of action. As the most rapidly acting schizontocide, artemisinin with its derivatives are in the forefront of the battle against malaria parasite. Forty one years after its extraction, the exact mechanism of action of artemisinin and its derivatives has not been unequivocally elucidated. Understanding its exact mode of action could help in new drug discovery that would circumvent the resistance mechanism of P. falciparum , present the additional and simpler tool of detecting and monitoring the spread of these resistant mutants by p roviding a surrogate marker of artemisinin resistance and, perhaps aid in the elimination of this menace. Artemisinin actions have been linked to the generation of radicals, which damage parasite vital biomolecules by alkylation, and oxidative stress in the microenvironment of its activation. Interference with the parasite heme-detoxification pathways, abolition of parasite mitochondrial inner membrane electropotential, inhibition of PfATP6 and apoptosis induction have all been documented as mediating artemisinin effects. At present, inhibition of PfATP6 as mediating artemisinin effects appears to attract the most attention. However, the picture is incomplete and sight should not be lost of equally strong and compelling facts implicating other molecular targets and the biochemical basis of the well demonstrated phenomenon of quiescence of ring forms under artemisinin pressure.
