Abstract: Despite the recent advances in its management using cytoreductive surgery and chemotherapy, ovarian cancer remains the most lethal gynecological malignancy. One possible treatment strategy that may improve patient outcome is the use of monoclonal antibodies (mAb) that selectively target tumor cells expressing tumor-associated antigens, and thus offer potential benefits such as avoiding the cytotoxic side effects in normal tissue caused by traditional chemotherapeutic agents. Based on the promising results of preclinical studies, various mAb are currently being evaluated in patients with ovarian cancer. Some of them have already demonstrated favorable clinical outcomes in phase I/II studies. However, in contrast to its use for hematological malignancies and certain solid malignancies such as breast and colorectal cancer, mAb-based therapy has not been convincingly proven to be clinically effective in patients with ovarian cancer. As the preclinical results of mAb's therapeutic effects on ovarian cancer have been encouraging, further investigations are needed to establish a more effective, specific, and less toxic treatment strategy for this malignancy. ... Read more

Abstract: Although thyroid carcinoma usually has an excellent prognosis, the lack of therapeutic options is an issue for patients that develop metastases and are resistant to radioiodine therapy. The development of novel molecular targeted therapies and the characterization of several proteins that have a crucial role in the carcinogenesis process of differentiated thyroid cancer have created an opportunity to design new clinical trials for this setting. Moreover, the encouraging initial results of first clinical trials have accelerated the development of placebo-controlled phase III studies that will assess the role of these new agents in the management of differentiated thyroid cancer. ... Read more

Abstract: No chemotherapy regimen showed a survival benefit better than 5-fluorouracil alone in a phase III trial for advanced gastric cancer in 1990s, and several new cytotoxic agents became available in late 1990s. Thereafter, a couple of phase III trials supported the substitution of infusional 5-fluorouracil by orally administered agents and the replacement of cisplatin by oxaliplatin in early 2000s. Furthermore, a substantial amount of information about the heterogeneity and the biological backgrounds of gastric cancer has been obtained from recent trials, and it is suggested that some cytotoxic agents would be well indicated. Trastuzumab has succeeded in showing a survival benefit for patients with Her-2 positive gastric cancer which accounts for about 10-20% of the cancer. This means that the door is opened to the new era of chemotherapy with molecular target agents and with individualization for advanced gastric cancer. The new approach in the development of molecular target agents, e.g., biomarker oriented strategy, for advanced gastric cancer should be studied in clinical trials in the near future. ... Read more

Abstract: Prostate cancer continues to represent a major health problem, and yet there is no effective treatment available for advanced metastatic disease. Thus, there is an urgent need for the development of more effective treatment modalities that could improve the outcome. Because prostate specific membrane antigen (PSMA), a transmembrane protein, is expressed by virtually all prostate cancers, and its expression is further increased in poorly differentiated, metastatic, and hormone-refractory carcinomas, it is a very attractive target. Molecules targeting PSMA can be labelled with radionuclides to become both diagnostic and/or therapeutic agents. The use of PSMA binding agents, labelled with diagnostic and therapeutic radio-isotopes, opens up the potential for a new era of personalized management of metastatic prostate cancer. ... Read more

Abstract: A new era in the treatment of systemic lupus erythematosus (SLE) may be dawning. Twelve years after the first approval of biologic therapy for patients with rheumatoid arthritis, the positive results of two large trials of a novel biologic therapy for SLE have raised hopes that a new approach to treatment may be at hand. This encouraging news follows several disappointments in trials of other biologic therapies and provides a timely moment to reflect on where we stand, what we have learned, and what may lie ahead. ... Read more

Abstract: Age-related Macular Degeneration (AMD) is the major cause of vision loss after age 50 in the United States. Although an important association of the complement cascade with AMD has recently been made, we still do not understand the pathogenesis of the disease. AMD is characterized by loss of the retinal pigment epithelium (RPE) within the macula (i.e., the center of the retina), and in turn, loss of the overlying foveal photoreceptors. Since RPE and photoreceptors can both be generated from stem cells using cell culture, there is hope for future cell replacement therapy. But, aging changes in Bruch's membrane, the scaffold on which the RPE are anchored, may complicate such therapy, and require surgical repair of Bruch's membrane to provide a suitable environment for cell survival and function. We have referred to such a multipronged approach of surgical reconstruction of the macular architecture in conjunction with cell transplantation as Maculoplasty. ... Read more

Abstract: If those of us privileged enough to have the opportunity to work towards curing human diseases had the power to design the ideal therapeutic molecule, the question would be what selection criteria would we choose? Arguably, at the top of the list would be four mandatory properties: specificity, potency, tolerability, and universality. So it should come as no surprise the momentum associated with the field of small interfering RNA (siRNA)-induced RNA Interference (RNAi) therapeutics has gained strength, as these molecules have shown exceptional promise in fulfilling all of these requirements. Unfortunately, siRNAs are too large, too charged, and too rigid to passively diffuse across the cellular membrane and thereby require a delivery system to enter cells. Thus, since its conception of working in human cells, siRNA delivery remains THE 800 Pound Gorilla in the room. The main complication yet to overcome is engineering delivery systems that are safe and efficient in systemically delivering siRNA molecules to the diseased tissue and across the cellular membrane of target cells. Currently, encapsulating the siRNA in nanoparticle and liposomal systems has risen to become the standard of delivery approaches. While generally speaking these delivery platforms offer significant advancements, our laboratory is committed to generating alternative siRNA delivery technologies that avoid nanoparticle packaging and allow siRNA molecules to be delivered as single, soluble entities. This brief review discusses the first of these technologies, a Peptide Transduction Domain-dsRNA Binding Domain (PTD-DRBD) fusion protein that avidly binds to the siRNA backbone to mask the negative charge and uses the PTD for macromolecular cellular delivery. ... Read more

Abstract: Treatment outcome for advanced-stage non-small cell lung cancer (NSCLC) is limited by empiric administration of cytotoxic chemotherapy. Recent advances in molecular genomics have revolutionized cancer management and, specifically, epidermal growth factor receptor (EGFR) mutation has become a potent biomarker for lung cancer, which predicts tumor response to and prolonged duration of disease control by EGFR tyrosine kinase inhibitors (TKI). The Iressa Pan-Asia Study (IPASS) is a randomized phase III study comparing gefitinib (EGFR TKI) with paclitaxel/carboplatin (standard chemotherapy) in Asian non-/light smokers with adenocarcinoma. Progression-free survival (PFS) in EGFR mutation-positive patients was longer with gefitinib than with chemotherapy (hazard ratio [HR], 0.48; 95% confidence interval [CI], 0.36-0.64; p<0.0001); in EGFR mutation-negative patients, PFS was longer with chemotherapy than with gefitinib (HR 2.85; 95% CI 2.05-3.98; p<0.0001). The findings are confirmed by one single-arm study and three other randomized studies. It has become clear that personalized medicine for NSCLC is feasible. This small step towards personalized medicine represents a paradigm shift in the management of NSCLC. ... Read more

Abstract: Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related deaths worldwide. About 50% of the patients present locally advanced or metastatic disease at the time of diagnosis. First line therapy usually consists of a combination of cisplatin or carboplatin with a third-generation agent (paclitaxel, docetaxel, gemcitabine, or vinorelbine) that results in less than 5% 5-year survival (Goldstraw et al., 2007). Recently a different approach based on histological subtype has been introduced in the first line treatment of NSCLC: in the non-squamous histotypes, cisplatin plus pemetrexed, compared to the cisplatin plus gemcitabine combination, showed a better outcome, leading to its introduction in the first line treatment setting. In recent years advances in the second and third line treatments have led to a prognostic improvement. Two cytotoxic agents, docetaxel and pemetrexed, are approved as NSCLC second line treatment, and a new class of drugs against specific molecular targets -- tyrosine Kinase inhibitors (TKI) -- has emerged as an alternative to conventional treatment. Many trials are ongoing to assess the activity of new drugs, alone or in combination with other agents, or new combinations of third-generation chemotherapeutic agents. ... Read more

Abstract: The loss of ability in controlling cell cycle leads to aberrant cell growth and is a hallmark of cancer cells. Cell cycle regulation and progression mainly rely on protein phosphorylation events, therefore cell cycle kinases have long been viewed as potential targets for anticancer strategies. Consistently, cell cycle kinases are often dysregulated in different types of human cancer. Despite years of research and attempts directed at inhibiting cell cycle kinases, none of these approaches has been successfully translated to the clinic to halt tumorigenesis. Here, we review several currently pursued strategies and highlight both current challenges and some recent findings, which might help to develop new, better conceived therapeutic approaches based on cell-cycle kinase inhibition. ... Read more