Development Of Molecular Targeted Therapies Research Articles

A Snapshot of Biomarkers in Psoriasis.

A persistent long-standing, inflammatory skin condition that is brought on by a variety of factors is psoriasis. It is distinguished by itchy, scaly, reddish plaques, particularly on areas of the body that are frequently chafed, including the extensor sites of the limbs. Recent developments in molecular-targeted therapy that use biologics or small-molecule inhibitors can effectively cure even the worst psoriatic indications. The outstanding clinical outcomes of treatment help to clarify the disease's detrimental consequences on quality of life. Biomarkers that identify deep remission are essential for developing uniform treatment plans. Blood protein markers such as AMPs that are consistently quantifiable can be very helpful in routine clinical practice. The metabolic pathways involve biomarkers that can not only help diagnose psoriasis in a clinical setting but also indicate its severity based on the levels present in the body. Machine learning and AI have made a diagnosis of the expression of genes as biomarkers more accessible. In this article, biomarkers, as well as their key role in psoriasis, are discussed.

3) Paradigm Shift in Management for Inflammatory Bowel Disease with the Development of Molecular-targeted Therapy

3) Paradigm Shift in Management for Inflammatory Bowel Disease with the Development of Molecular-targeted Therapy

3) Paradigm Shift in Management for Inflammatory Bowel Disease with the Development of Molecular-targeted Therapy

3) Paradigm Shift in Management for Inflammatory Bowel Disease with the Development of Molecular-targeted Therapy

Current research status and progress in molecular subty-ping of pancreatic cancer

Rational molecular subtyping of pancreatic cancer based on genome, transcriptome, proteomics and metabolomics data, in combination with systematic biological analysis, have greatly enriched the traditional histopathological typing methods based on morphology. The introduction of molecular subtyping reflects the progress in deep understanding of the essence of tumorigenesis of pancreatic cancer, providing a necessary foundation for the development of molecular targeted therapy and implementation of precision medicine. Therefore, molecular subtyping of pancreatic cancer has broad application prospects. The current article reviews the current research status and recent progress of molecular subtyping of pancreatic cancer, and discusses the clinical significance of different subtyping methods. Key words: Pancreatic neoplasms; Pancreatic can-cer; Molecular subtypes; Molecular targeted therapy; Progress

Experience of Surgical Management of Gastrointestinal Stromal Tumors at a Tertiary Hospital of Nepal

Gastrointestinal stromal tumors (GISTs) are rare malignancies but a most common mesenchymal tumor. A multidisciplinary team approach is the optimal care of GIST patients after the remarkable outcomes with the development of molecular-targeted therapy. The objective is to determine the clinic-pathological spectrum and risk category of GIST along with perioperative outcomes. This is a retrospective review of GIST patients between September 2015 – August 2018 at Tribhuvan University Teaching Hospital (TUTH), Kathmandu, Nepal. Patients’ clinical data, histopathology, immunohistochemistry (IHC) and outcomes were recorded and analyzed. A total of 42 GIST patients were identified with age (19-81 years) and 69% were males. Stomach (35.7%) was the most common site followed by small bowel (23.8%) and duodenum (14.3%). Pain (40.5%) followed by bleeding (30.9%) were major indications. Max tumor dimensions were ranging from 2.8- 30 cm and median mitotic figures were 3 (0-35). Patients were stratified as high, intermediate, low and very low risk (36%, 32%, 32%, and 0% respectively). The majority were managed surgically out of which three cases underwent preoperative angioembolization. CD 117 was positive in 90.5%. Neoadjuvant imatinib given in 2 cases while adjuvant imatinib given in 18 cases. Over a median follow up of 18 months four patients expired while 32 had no issues. Surgical resection is the preferred choice of treatment with or without the molecular targeted drug therapy. Most tumors fall in the high-risk category.

Clinical, Pathological, and Ethical Considerations for the Conduct of Clinical Trials in Dogs with Naturally Occurring Cancer: A Comparative Approach to Accelerate Translational Drug Development.

The role of comparative oncology in translational research is receiving increasing attention from drug developers and the greater biomedical research community. Pet dogs with spontaneous cancer are important and underutilized translational models, owing to dogs' large size and relative outbreeding, combined with their high incidence of certain tumor histotypes with significant biological, genetic, and histological similarities to their human tumor counterparts. Dogs with spontaneous tumors naturally develop therapy resistance and spontaneous metastasis, all in the context of an intact immune system. These fundamental features of cancer biology are often lacking in induced or genetically engineered preclinical tumor models and likely contribute to their poor predictive value and the associated overall high failure rate in oncology drug development. Thus, the conduct of clinical trials in pet dogs with naturally occurring cancer represents a viable surrogate and valuable intermediary step that should be increasingly incorporated into the cancer drug discovery and development pipeline. The development of molecular-targeted therapies has resulted in an expanded role of the pathologist in human oncology trials, and similarly the expertise of veterinary pathologists will be increasingly valuable to all phases of comparative oncology trial design and conduct. In this review, we provide a framework of clinical, ethical, and pathology-focused considerations for the increasing integration of translational research investigations in dogs with spontaneous cancer as a means to accelerate clinical cancer discovery and drug development.

HEG1 is a novel mucin-like membrane protein that serves as a diagnostic and therapeutic target for malignant mesothelioma

The absence of highly specific markers for malignant mesothelioma (MM) has served an obstacle for its diagnosis and development of molecular-targeting therapy against MM. Here, we show that a novel mucin-like membrane protein, sialylated protein HEG homolog 1 (HEG1), is a highly specific marker for MM. A monoclonal antibody against sialylated HEG1, SKM9-2, can detect even sarcomatoid and desmoplastic MM. The specificity and sensitivity of SKM9-2 to MM reached 99% and 92%, respectively; this antibody did not react with normal tissues. This accurate discrimination by SKM9-2 was due to the recognition of a sialylated O-linked glycan with HEG1 peptide. We also found that gene silencing of HEG1 significantly suppressed the survival and proliferation of mesothelioma cells; this result suggests that HEG1 may be a worthwhile target for function-inhibition drugs. Taken together, our results indicate that sialylated HEG1 may be useful as a diagnostic and therapeutic target for MM.

Controversies: molecular vs. clinical systemic sclerosis classification

Systemic sclerosis (SSc) is a multisystem chronic disease characterized by the three cardinal pathological features, including autoimmunity/inflammation, vasculopathy, and fibrosis, with unknown etiology. Individual patients manifest these three components to variable degrees, resulting in the diverse heterogeneity of clinical presentation. The classification of SSc patients into relatively homogenous subtypes is helpful in the setting of daily clinical practice and the field of clinical and basic research. The classification of SSc has been continuously discussed over four decades based on the clinical and laboratory features, especially the extent of skin sclerosis and disease-related autoantibodies. This clinical classification system enables clinicians to provide general advice regarding prognosis and risk for internal organ disease, but only permits estimates of outcomes informed by population-based studies. On the other hand, the recent decade has seen much progress in the understanding of molecular aspects of SSc complex pathology, raising a discussion on molecular classification of SSc. The development of molecular targeting therapies, especially biologics, further strengthens the importance of molecular classification which aids the identification of potential responders for each treatment. Although a careful validation study is required for molecular classification of SSc due to its large heterogeneity, the advance of molecular classification would introduce a further modification into SSc classification system in the near future. Importantly, clinical and molecular classifications are not mutually exclusive, therefore the combination would facilitate the development of a better classification system of this complex heterogeneous disorder that is useful in both the clinical setting and research studies.

Update on stem cell transplantation for acute leukemias.

The treatment strategies for acute leukemia are undergoing very rapid change. Particularly for last 10 years, due to the rapid development of molecular targeted therapy and cell/gene therapies, the role of HSCT in the treatment scheme of acute leukemia has been changing. In the author's view, these recent changes should secure the role of HSCT in the comprehensive treatment scheme of acute leukemia. By appropriately combining the new agents with HSCT, therapy for acute leukemia is anticipated to become more effective. HSCT will provide the centerpiece for the treatment scheme, by setting up the "platform" for further interventions. Keeping these changes in mind, transplant physicians should now be exploring new areas of research such as interactions between these new agents and GVHD/GVL.

Molecular mechanisms of peritoneal dissemination in gastric cancer.

Peritoneal dissemination represents a devastating form of gastric cancer (GC) progression with a dismal prognosis. There is no effective therapy for this condition. The 5-year survival rate of patients with peritoneal dissemination is 2%, even including patients with only microscopic free cancer cells without macroscopic peritoneal nodules. The mechanism of peritoneal dissemination of GC involves several steps: detachment of cancer cells from the primary tumor, survival in the free abdominal cavity, attachment to the distant peritoneum, invasion into the subperitoneal space and proliferation with angiogenesis. These steps are not mutually exclusive, and combinations of different molecular mechanisms can occur in each process of peritoneal dissemination. A comprehensive understanding of the molecular events involved in peritoneal dissemination is important and should be systematically pursued. It is crucial to identify novel strategies for the prevention of this condition and for identification of markers of prognosis and the development of molecular-targeted therapies. In this review, we provide an overview of recently published articles addressing the molecular mechanisms of peritoneal dissemination of GC to provide an update on what is currently known in this field and to propose novel promising candidates for use in diagnosis and as therapeutic targets.

Management strategies for hepatocellular carcinoma: old certainties and new realities

Hepatocellular carcinoma (HCC) is a highly prevalent disease ranking among the ten most common cancers worldwide with increasing trend of incidence in most developed countries. The great healthcare costs and economic burden of HCC dictate proper preventive interventions as well as surveillance and screening programs to decrease disease incidence and allow early diagnosis. HCC treatment outcomes are affected by several variables, including liver function, patient's performance status, and tumor stage. In line with the Barcelona Clinic Liver Cancer (BCLC) staging curative treatments, such as surgery or radio-frequency ablation, are indicated in early-stage HCC (BCLC-A), and the noncurative treatments are indicated in intermediate and advanced stages of HCC (BCLC-B, C). Transarterial chemoembolization (TACE) represents the treatment of choice for intermediate-stage HCC with Child-Pugh A cirrhosis, and the long-term survival after liver transplantation is inferior to that of early-stage HCCs. In advanced-stage HCC or when complete necrosis is not achieved or early recurrence after TACE develops, individualized treatments such as systemic treatment or combined radiation therapy are indicated. The increasing knowledge of the genomic landscape of HCC and the development of molecular-targeted therapies is heading toward expanding the armamentarium for HCC management.

Managing pregnancy in chronic myeloid leukaemia.

Over the past decade, we have witnessed significant advances in knowledge of the biology and treatment of chronic myeloid leukaemia (CML). The development of molecular-targeted therapy with tyrosine kinase inhibitors (TKIs) has fundamentally changed the outcome of this disease. Treatment with TKIs is now the standard of care in patients with CML and has dramatically improved long-term survival in the majority of patients. Patients who achieve major molecular response (MMR) after 2 years of treatment with imatinib have survival rates comparable to those of the general population. The success of TKIs has led to durable molecular response and possibility of normal life expectancies, such that it is now timely to address quality of life aspects such as fertility, pregnancy and family planning. Pregnancy in CML presents specific management and therapeutic challenges for the patient and the physician. Despite the recent treatment advances, we still have limited data on the safety of TKIs in pregnancy and its effect on fertility. However, there is a cause for concern and heightened awareness following the occurrence of a constellation of rare congenital malformations and spontaneous abortions in association with imatinib therapy. When a patient becomes pregnant whilst receiving TKI therapy, the difficulty lies in balancing the risk to the foetus of continuing therapy versus the risk to the patient of treatment interruption and potentially losing optimal disease response. All couples should be counselled on the risks associated with pregnancy whilst receiving TKI therapy. This is an essential aspect in patient care and frequently not emphasized enough by physicians. At the time of diagnosis, fertility preservation should be discussed with both male and female patients of childbearing potential. They should be made aware of fertility options which are available such as semen cryopreservation, ovarian or oocyte retrieval and storage and embryo cryopreservation in view of the potential detrimental effect of TKIs on fertility and gonadal function. The recommendation given to patients planning pregnancy differs according to their disease response to TKI therapy, which is the most important prognostic factor in CML.

Phosphatidylinositol 3-kinase-AKT-mammalian target of rapamycin (PI3K-Akt-mTOR) signaling pathway in non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) is a devastating disease with poor prognosis. Systemic chemotherapy has been the mainstay of treatment in advanced disease for many decades. Personalized targeted therapy such as epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs) and crizotinib has significantly changed the treatment paradigm in NSCLC. The future success of development of molecular targeted therapy relies on the understanding of signal transduction pathways. The PI3K-Akt-mTOR pathway is commonly deregulated in human malignancy including NSCLC. Therefore, this pathway is a target for many therapeutic developments. This review will provide an overview of PI3K-Akt-mTOR signaling pathway, genetic alterations activating the pathway and clinical therapeutic development of pathway inhibitors.

Disease‐specific mutations in mature lymphoid neoplasms: Recent advances

Mature lymphoid neoplasms (MLN) are clinically and pathologically more complex than precursor lymphoid neoplasms. Until recently, molecular characterization of MLN was mainly based on cytogenetics/fluorescence in situ hybridization, allele copy number, and mRNA expression, approaches that yielded scanty gene mutation information. Use of massive parallel sequencing technologies has changed this outcome, and now many gene mutations have been discovered. Some of these are considerably frequent in, and substantially specific to, distinct MLN subtypes, and occur at single or several hotspots. They include the V600E BRAF mutation in hairy cell leukemia, the L265P MYD88 mutation in Waldenström macroglobulinemia, the G17V RHOA mutation in angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma, not otherwise specified, and the Y640F//D661Y/V/H/I//N647I STAT3 mutations in T-cell large granular lymphocytic leukemia. Detecting these mutations is highly valuable in diagnosing MLN subtypes. Defining these mutations also sheds light on the molecular pathogenesis of MLN, furthering development of molecular targeting therapies. In this review, we focus on the disease-specific gene mutations in MLN discovered by recent massive sequencing technologies.

Use of regulators and inhibitors of Pim-1, a serine/threonine kinase, for tumour therapy (review).

Pim-1 is a proto-oncogene that encodes a serine/threonine kinase that is overexpressed in a range of haematopoietic malignancies and solid cancers. Pim-1 expression is tightly regulated by multiple biomolecules at different levels. Several lines of evidence have indicated that dysregulation of Pim-1 can interfere with the cell cycle and apoptosis to promote malignant transformation of a number of types of tumour. Thus, investigation of Pim-1 regulation may provide important theoretical guidance for the development of molecular targeting therapies and drug treatments for Pim-1‑associated diseases. Regulators of Pim-1 expression, include microRNAs, oestrogen, inecalcitol, adenosine triphosphate (ATP) mimetic inhibitors and ATP competitive inhibitors of Pim-1. Combinations of inhibitors of Pim-1 expression and Pim-1‑specific inhibitors may provide novel therapies for cancer patients and directions for cancer treatment.

Molecular targeted therapy of malignant pleural mesothelioma

Malignant pleural mesothelioma (MPM) is a rare form of cancer with latency period of 20 years,and it is now a period of high flows of MPM.It is often detected in late stages,and the efficacy of surgery,radiotherapy and second/third-line chemotherapy still remains unknown except the classical first-line chemotherapy regimen contains pemetrexed and cisplatin.With the development of molecular targeted therapy,a new direction for individual therapy of MPM patient has been provided for the past few years. Key words: Genes; Neoplasms; Malignant pleural mesothelioma; Molecular targeted therapy

Efficacy of chemotherapy in limited-disease small-cell lung cancer

SUMMARY Small-cell lung cancer (SCLC) accounts for approximately 13% of all lung cancers, and limited-disease SCLC is defined as a disease that can be encompassed within a tolerable radiation field. Concurrent chemoradiotherapy is considered to be the standard treatment for limited-disease SCLC. In both concurrent and consolidation chemoradiotherapies, the combination of etoposide and cisplatin is considered to be a standard chemotherapy regimen. To develop novel treatment for SCLC, several clinical trials of molecular-targeted therapy or immunotherapy have been reported. However, no molecular-targeted drug has shown clinical activity in limited-disease SCLC. In future studies, understanding the molecular profile of SCLC will be necessary for the development of molecular-targeted therapies for SCLC. This review provides an overview of chemotherapy regimens for limited-disease SCLC.

TMEM158 and FBLP1 as novel marker genes of cisplatin sensitivity in non-small cell lung cancer cells

ABSTRACTEven after development of molecular targeting therapies, platinum-based chemotherapy is still a standard care for treatment of locally advanced non-small cell lung cancer (NSCLC). So far, critical molecular markers capable to predict the therapeutic response in NSCLC patients remain undetermined. We here attempted to identify novel biomarker genes for cisplatin (CDDP) for a tailored therapy. Initial screening to explorer association of IC50 values of CDDP obtained by MTT assay and gene expression levels measured with oligonucleotide microarray and real-time RT-PCR provided 6 candidate genes, namely, NUBPL, C9orf30, ZNF12, TMEM158, GSK3B, and FBLP1 using 9 lung cancer cells consisting of 3 small and 6 NSCLC cells. These 6 genes together with 5 reported biomarkers, i.e., GSTP1, ERCC1, BRCA1, FRAP1, and RRM1, were subjected to a linear regression analysis using 12 NSCLC cell lines including 6 additional NSCLC cells: only FBLP1 and TMEM158 genes showed positive associations with statistical significances (P = .016 and .026, respectively). The biological significance of these genes was explored by in vitro experiments: Knockdown experiments in PC-9/CDDP cells revealed that the reduced expression of TMEM158 significantly decreased the chemo-resistance against CDDP (P <.0001), while 2 transformants of PC-6 cells stably over-expressing FBLP1 resulted in an enhanced resistance to CDDP (P = .004 and P = .001). Furthermore, a stepwise multiple regression analysis demonstrated the best prediction formula could be fixed when we used expression data of TMEM158 and FBLP1 (R2 = 0.755, P = .0018). TMEM158 and FBLP1 may be powerful predictive biomarkers for CDDP therapy in NSCLC.

Expression of hypoxia-inducible protein 2 in renal cell carcinoma: A promising candidate for molecular targeting therapy

This study investigated the expression of hypoxia-inducible protein 2 (HIG2), a novel renal cell carcinoma (RCC)-associated molecule and an essential growth factor for RCC, in kidneys to elucidate its clinical significance in RCC. An immunohistochemical study of HIG2 was conducted in 93 surgical samples of RCC tissues and 10 samples of normal kidney tissues obtained after nephrectomies for localized RCC. HIG2 expression was also correlated with clinicopathological characteristics and survival. Only faint or weak immunostaining for HIG2 was observed in normal kidney samples. HIG2 expression was found in 86% of RCC tissues (80/93). When analyzed by histological type, positive staining for HIG2 was detected in all papillary (7/7), chromophobe (1/1) and cyst-associated (3/3) RCC. In contrast, the HIG2 expression was observed in 85% of clear cell (68/80) and 50% of spindle cell (1/2) RCC. Labeling indices were 74.1, 45.4, 39, 24.8 and 12.1% in papillary, spindle, clear cell, cyst-associated and chromophobe RCC, respectively. A significant increase in HIG2 expression was noted in RCC tissues obtained from patients with high stage RCC, lymph node metastasis and high nuclear grade (p<0.001, p<0.02 and p<0.006, respectively). RCC patients with a negative HIG2 staining had prolonged 5-year cancer-specific survival. In conclusion, HIG2 expression was extensively observed in RCC tissues and was higher in advanced RCC, suggesting that HIG2 is a candidate for the development of molecular targeting therapy.

Combined modality therapy for local advanced non-small cell lung cancer

This paper reviews the latest developments in radiotherapy, chemotherapy and chemoradiotherapy for local advanced non-small cell lung cancer in the past years. Radiotherapy, includes conventional fractionated radiotherapy, accelerated hyperf-raction radiotherapy and three-dimensional radiotherapy etc.Chemotherapy, includes the analysis of effects of various chemotherapeutic regimens, recommending the reasonable methods of chemotherapy and chemoradiotherapy and the development of molecular targeted therapy. Sequential chemoradiotherapy and concurrent chemoradiotherapy show advantagement chemoradiotherapy on the local control rate and survival rate. Key words: Carcinoma, non-small-cell lung; Radiotherapy; Drug therapy; Combined modality therapy