Prognostic Factors in the Era of Targeted Therapies in CLL

Purpose of Review

Chronic lymphocytic leukemia is heterogeneous disease characterized by a variable clinical course that is greatly influenced by various patient and disease characteristics. Over the last two decades, advent of new diagnostic methodologies has led to the identification of several factors of prognostic and predictive relevance. Furthermore, recent advances in next-generation sequencing techniques has identified recurrent novel mutations in NOTCH1, SF3B1, BIRC3, and ATM genes whose role as prognostic and predictive markers is currently being investigated. These biologic markers carry new prognostic information and their incorporation into prognostic scoring systems will likely lead to refined multi-parameter risk models.

Recent Findings

While the prognostic impact of many of the most commonly used markers on clinical outcomes in patients treated with chemo-immunotherapy is well documented, it is important to review their predictive and prognostic role in the era of novel targeted therapies.

Summary

This article will discuss the currently available information on the clinical relevance of prognostic markers in patients treated with novel targeted therapies.

     

Targeted next-generation sequencing identifies clinically relevant mutations in patients with chronic neutrophilic leukemia at diagnosis and blast crisis

Purpose

Chronic neutrophilic leukemia is a rare form of myeloproliferative neoplasm characterized by mature neutrophil hyperleukocytosis. The majority of patients harbor somatic mutations of CSF3R gene and are potentially amenable to targeted therapy with JAK inhibitors. The incidence and clinical significance of additional mutations requires clarification.

Materials and methods

A next-generation sequencing approach for myeloid malignancy-associated mutations was applied to diagnostic and matched blast crisis samples from four chronic neutrophilic leukemia patients.

Results

Next-generation sequencing confirmed the CSF3R T618I in all patients with identification of concurrent SRSF2, SETBP1, NRAS and CBL mutations at diagnosis. At blast crisis, clonal evolution was evidenced by an increased CSF3R T618I allele frequency and by loss or acquisition of CBL and NRAS mutations.

Conclusion

The diagnostic utility of a targeted next-generation sequencing approach was clearly demonstrated with the identification of additional mutations providing the potential for therapeutic stratification of chronic neutrophilic leukemia patients.

     

Expression Analysis of Survivin and XIAP in Gallbladder Cancer: a Case-control Study in Indo-Gangetic Plain

Purpose

Gallbladder cancer is a highly mortal disease with poor prognosis because of late presentation of disease. Survivin and X-linked inhibitor of apoptosis (XIAP) are one of the two important members of inhibitors of apoptosis. Thus, this study aimed to look at the expression of Survivin and XIAP in gallbladder cancer patients.

Methods

Survivin and XIAP expression were investigated in tissues of gallbladder cancer patients (40 cases) and compared with cholelithiasis as control (40 cases) by using immunohistochemistry. Their expression was correlated with clinicopathological parameters.

Results

Significantly higher (p < 0.05), Survivin protein was expressed in gallbladder cancer (n = 67.5%) than control (n = 35%). But it did not show any significant association with any of the clinicopathological parameter while XIAP was not expressed in the GBC patients (p > 0.05).

Conclusion

Overexpression of Survivin in gallbladder cancer suggests its possible role and association with poor prognosis. But XIAP has not been found to be associated with gallbladder carcinogenesis.

     

Homologous recombination deficiency and host anti-tumor immunity in triple-negative breast cancer

Purpose

Triple-negative breast cancer (TNBC) is associated with worse outcomes relative to other breast cancer subtypes. Chemotherapy remains the standard-of-care systemic therapy for patients with localized or metastatic disease, with few biomarkers to guide benefit.

Methods

We will discuss recent advances in our understanding of two key biological processes in TNBC, homologous recombination (HR) DNA repair deficiency and host anti-tumor immunity, and their intersection.

Results

Recent advances in our understanding of homologous recombination (HR) deficiency, including FDA approval of PARP inhibitor olaparib for BRCA1 or BRCA2 mutation carriers, and host anti-tumor immunity in TNBC offer potential for new and biomarker-driven approaches to treat TNBC. Assays interrogating HR DNA repair capacity may guide treatment with agents inducing or targeting DNA damage repair. Tumor infiltrating lymphocytes (TILs) are associated with improved prognosis in TNBC and recent efforts to characterize infiltrating immune cell subsets and activate host anti-tumor immunity offer promise, yet challenges remain particularly in tumors lacking pre-existing immune infiltrates. Advances in these fields provide potential biomarkers to stratify patients with TNBC and guide therapy: induction of DNA damage in HR-deficient tumors and activation of existing or recruitment of host anti-tumor immune cells. Importantly, these advances provide an opportunity to guide use of existing therapies and development of novel therapies for TNBC. Efforts to combine therapies that exploit HR deficiency to enhance the activity of immune-directed therapies offer promise.

Conclusions

HR deficiency remains an important biomarker target and potentially effective adjunct to enhance immunogenicity of ‘immune cold’ TNBCs.

     

<Emphasis Type="Italic">PIK3CA</Emphasis> mutations and <Emphasis Type="Italic">TP53</Emphasis> alterations cooperate to increase cancerous phenotypes and tumor heterogeneity

Background/purpose

The combined contributions of oncogenes and tumor suppressor genes toward carcinogenesis remain poorly understood. Elucidation of cancer gene cooperativity can provide new insights leading to more effective use of therapies.

Experimental design/Methods

We used somatic cell genome editing to introduce singly and in combination PIK3CA mutations (E545K or H1047R) with TP53 alterations (R248W or knockout), to assess any enhanced cancerous phenotypes. The non-tumorigenic human breast epithelial cell line, MCF10A, was used as the parental cell line, and resultant cells were assessed via various in vitro assays, growth as xenografts, and drug sensitivity assays using targeted agents and chemotherapies.

Results

Compared to single-gene-targeted cells and parental controls, cells with both a PIK3CA mutation and TP53 alteration had increased cancerous phenotypes including cell proliferation, soft agar colony formation, aberrant morphology in acinar formation assays, and genomic heterogeneity. Cells also displayed varying sensitivities to anti-neoplastic drugs, although all cells with PIK3CA mutations showed a relative increased sensitivity to paclitaxel. All cell lines remained non-tumorigenic.

Conclusions

This cell line panel provides a resource for further elucidating cooperative genetic mediators of carcinogenesis and response to therapies.

     

A high frequency of PALB2 mutations in Jamaican patients with breast cancer

Purpose

Jamaica is an island nation with one of the highest breast cancer incidence rates in the Caribbean (40/100,000 per year). The contribution of cancer susceptibility gene mutations to the burden of breast cancer in Jamaica has not yet been explored. We sought to determine the prevalence of germline mutations in BRCA1, BRCA2, and PALB2 in 179 unselected Jamaican women with breast cancer.

Methods

We sequenced the entire coding regions of BRCA1, BRCA2, and PALB2 for all the study subjects.

Results

Overall, 8 of 179 patients (4.5%) had a mutation in one of the three genes: one in BRCA1, two in BRCA2, and five in PALB2.

Conclusions

These data suggest that in addition to BRCA1 and BRCA2, PALB2 should be included in genetic testing for breast cancer patients in Jamaica.

     

Genetic mutation analysis of the malignant transformation of sinonasal inverted papilloma by targeted amplicon sequencing

Background

The mechanism underlying the malignant transformation of inverted papilloma (IP) has not yet been elucidated.

Methods

To clarify the genes responsible for the malignant transformation, we analyzed 10 cases of IP, 8 of IP with dysplasia, and 11 of squamous cell carcinoma (SCC) by targeted amplicon sequencing.

Results

The number of mutant genes increased in the order of IP?<?dysplasia?<?SCC. Significant differences were observed in the mutation rates of three genes (KRAS, APC and STK11) in particular. TP53 was altered frequently in each group and might be involved in malignant transformation based on to the site of the mutation. A comparison of the genetic variants by region of IP tissue among patients with IP alone, and those with dysplasia or SCC revealed significant differences in the mutation rate of the KRAS gene.

Conclusion

Identification of genetic mutations in KRAS is effective for predicting the malignant transformation of IP.

     

<Emphasis Type="Italic">WT1, MSH6</Emphasis>, <Emphasis Type="Italic">GATA5</Emphasis> and <Emphasis Type="Italic">PAX5</Emphasis> as epigenetic oral squamous cell carcinoma biomarkers - a short report

Purpose

Oral squamous cell carcinoma (OSCC) is a frequently occurring aggressive malignancy with a heterogeneous clinical behavior. Based on the paucity of specific early diagnostic and prognostic biomarkers, which hampers the appropriate treatment and, ultimately the development of novel targeted therapies, we aimed at identifying such biomarkers through a genetic and epigenetic analysis of these tumors.

Methods

93 primary OSCCs were subjected to DNA copy number alteration (CNA) and methylation status analyses using methylation-specific multiplex ligation-dependent probe amplification (MS-MPLA). The genetic and epigenetic OSCC profiles obtained were associated with the patients’ clinic-pathological features.

Results

We found that WT1 gene promoter methylation is a predictor of a better prognosis and that MSH6 and GATA5 gene promoter methylation serve as predictors of a worse prognosis. GATA5 gene promoter methylation was found to be significantly associated with a shorter survival rate. In addition, we found that PAX5 gene promoter methylation was significantly associated with tongue tumors. To the best of our knowledge, this is the first study that highlights this specific set of genes as epigenetic diagnostic and prognostic biomarkers in OSCC.

Conclusions

Our data highlight the importance of epigenetically assessing OSCCs to identify key genes that may serve as diagnostic and prognostic biomarkers and, potentially, as candidate therapeutic targets.

     

Magnetic resonance imaging identifies early effects of sunitinib treatment in human melanoma xenografts

Background

Antiangiogenic treatment may change the tumor microenvironment and hence influence the effect of conventional therapies. The potential of diffusion weighted magnetic resonance imaging (DW-MRI) and dynamic contrast enhanced MRI (DCE-MRI) in assessing microenvironmental effects of sunitinib treatment was investigated in this preclinical study.

Methods

Sunitinib-treated and untreated A-07 tumors were subjected to DW-MRI and DCE-MRI, and parametric images of ADC and K^trans were produced. Microvascular density, hypoxic fraction, and necrotic fraction were assessed from immunohistochemical preparations, and tumor interstitial fluid pressure (IFP) was assessed with probe measurement.

Results

Sunitinib-treated tumors showed reduced microvascular density, increased hypoxic fraction, increased necrotic fraction, increased ADC, and reduced K^trans, but did not differ from untreated tumors in growth rate and IFP.

Conclusions

Sunitinib treatment affected the tumor microenvironment without affecting tumor size. DW-MRI and DCE-MRI were sensitive to the sunitinib-induced changes in the tumor microenvironment.

     

The Future of Combination Therapies for Peripheral T Cell Lymphoma (PTCL)

Purpose of Review

Peripheral T cell lymphoma is a rare heterogeneous group of diseases which are characterized by poor outcomes to treatment and short overall survival. In the past decade, several new therapies targeting T cell biology have been approved in the relapsed setting. These new therapies, such as pralatrexate, romidepsin, belinostat, and brentuximab vedotin, have begun to make their way into practice. Despite these advances, outcomes have not changed dramatically. In recent years, efforts have been made to incorporate these new therapies into combination strategies to treat this challenging disease entity. Herein we will review some of the latest developments.

Recent Findings

With the new WHO classification, discrete entities of PTCL are now being identified by molecular and phenotypic markers. This new classification is critical to our ability to define disease entities which may respond to certain classes of targeted therapy. Some such mutations include genes controlling epigenetics (TET2, IDH2, DNMT3A, RHOA, CD28). As such, epigenetic therapies such as histone deacetylase (HDAC) inhibitors have become the platform to which other novel therapies or chemotherapy has been added. Early phase clinical studies have demonstrated that combination therapy with romidepsin plus other agents known to have activity in T cell lymphoma have enhanced clinical benefit for this group of diseases. In addition, the antibody drug conjugate, brentuximab vedotin has been shown to have potent activity in T cell lymphomas expressing CD30. This drug is being studied as well with other targeted therapies and chemotherapy in an effort to improve response rates and progression-free survival.

Summary

Although T cell lymphomas remain a highly challenging group of diseases to treat, new efforts to leverage drugs that discretely target the biology that drives T cell lymphomagenesis in combination provide hope that improved outcomes may be realized in the near future.

     

Sensitive methods for screening of the <Emphasis Type="Italic">MEK1</Emphasis> gene mutations in patients with central nervous system metastases of non-small cell lung cancer

Background

The mitogen-activated protein kinases 1 and 2 (MEK1, MEK2) are fundamental partners in the RAS–RAF–MEK–ERK pathway that is involved in regulation of cell proliferation, differentiation and survival. Downregulation of the MEK cascades has been implicated in acquiring of the malignant phenotype in various cancers. Somatic mutations in MEK1 gene (substitutions K57N, Q56P, D67N) were described in <1 % of non-small cell lung cancer (NSCLC) and they were more commonly reported in adenocarcinoma patients with current or former smoking status.

Materials and methods

In the following study, we assessed the MEK1 gene mutations in 145 FFPE tissue samples from central nervous system (CNS) metastases of NSCLC using HRM-PCR and ASP-qPCR techniques. The studied group was heterogeneous in terms of histopathology and smoking status. The prevalence of the MEK1 gene mutation was correlated with the occurrence of mutations in KRAS, EGFR, DDR2, PIK3CA, NRAS, HER2, AKT1 and PTEN genes.

Results

Using HRM and ASP-qPCR methods we identified one (0.7 %; 1/145) MEK1 substitution (Q56P) in CNS metastases of NSCLC. The mutation was identified in a single, 50-year-old, current smoking men with adenocarcinoma (1.25 %; 1/80 of all adenocarcinomas).

Conclusions

According to the current knowledge, the incidence of MEK1 gene mutation in CNS metastatic lesion of NSCLC is the first such report worldwide. The analysis of gene profile in cancer patients may extend the scope of molecularly targeted therapies used both in patients with primary and metastatic tumors of NSCLC.

     

Evaluation of <Emphasis Type="Italic">ALK</Emphasis> gene rearrangement in central nervous system metastases of non-small-cell lung cancer using two-step RT-PCR technique

Purpose

RT-PCR technique has showed a promising value as pre-screening method for detection of mRNA containing abnormal ALK sequences, but its sensitivity and specificity is still discussable. Previously, we determined the incidence of ALK rearrangement in CNS metastases of NSCLC using IHC and FISH methods.

Materials

We evaluated ALK gene rearrangement using two-step RT-PCR method with EML4-ALK Fusion Gene Detection Kit (Entrogen, USA). The studied group included 145 patients (45 females, 100 males) with CNS metastases of NSCLC and was heterogeneous in terms of histology and smoking status.

Results

21% of CNS metastases of NSCLC (30/145) showed presence of mRNA containing abnormal ALK sequences. FISH and IHC tests confirmed the presence of ALK gene rearrangement and expression of ALK abnormal protein in seven patients with positive result of RT-PCR analysis (4.8% of all patients, 20% of RT-PCR positive patients). RT-PCR method compared to FISH analysis achieved 100% of sensitivity and only 82.7% of specificity. IHC method compared to FISH method indicated 100% of sensitivity and 97.8% of specificity. In comparison to IHC, RT-PCR showed identical sensitivity with high number of false positive results.

Conclusion

Utility of RT-PCR technique in screening of ALK abnormalities and in qualification patients for molecularly targeted therapies needs further validation.

     

Therapie im Stadium IV des nichtkleinzelligen Lungenkarzinoms mit Treibermutation

Background

Systemic treatment of non-small cell lung cancer (NSCLC) is currently undergoing a paradigmatic change with impressive dynamics. Patients with advanced disease are treated based on the analysis of biomarkers either with immunotherapy, a combination of immunotherapy with chemotherapy or with driver mutation-directed targeted drugs. Treatment of acquired resistance remains a particular challenge. An increasing knowledge of the molecular mechanisms underlying resistance enables the development of more potent inhibitors.

Objective

This review focuses on the state of the art and current developments in targeted therapy of advanced stage NSCLC.

Material and methods

This review is based on the summary and interpretation of publications on preclinical and clinical studies in the field of targeted treatment of advanced NSCLC.

Results and conclusion

Targeted treatments against activating mutations in the EGFR and BRAF genes as well as ALK and ROS1 fusions define the standard first line treatment for approximately 15?% of patients with advanced NSCLC. In retrospective analyses this development has led to a substantially prolonged overall survival in these subgroups. Targeted therapies against further aberrations are in clinical evaluation and a targeted treatment is currently available for approximately 30% of patients. Next generation inhibitors are characterized by a high effectiveness against tumors with acquired resistance to tyrosine kinase inhibitors (TKI) and improved tolerability and are increasingly being used as first line treatment. In order to understand the molecular causes and to select the most effective treatment, rebiopsies play a special role in resistance.

     

Germline promoter hypermethylation in <Emphasis Type="Italic">BRCA1</Emphasis> and <Emphasis Type="Italic">BRCA2</Emphasis> genes is not present in hereditary breast cancer patients

Purpose

Germline promoter hypermethylation of BRCA1 and BRCA2 genes is an alternative event of gene silencing that has not been widely investigated in hereditary breast and ovarian cancer (HBOC) syndrome.

Methods

We analyzed germline BRCA promoter hypermethylation in HBOC patients with and without BRCA mutations and control subjects, using a recently developed BRCA methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) assay.

Results

Neither the patients tested nor the control subjects showed germline hypermethylation of the BRCA1 and BRCA2 promoter regions analyzed.

Conclusions

Despite the results achieved at somatic levels by other researchers, these were not confirmed in our study at the germline level. Our results show the need to establish more predictive CpG sites in the BRCA promoter regions to optimize the MS-MLPA assayfor the detection of germline hypermethylation as an effective pre-screening tool for whole-BRCA genetic analysis in HBOC, because we can not rule out the existence of germline promoter hypermethylation in BRCA.

     

体外不同分化程度滋养细胞对靶向微泡造影剂结合特性的影响(英文)

Objective:In this study, we investigated the in vitro binding capacity of β-HCG antibody targeted SonoVue microbubbles to trophoblasts with distinct differentiation in order to explore the possibility of utility of targeted SonoVue microbubbles imaging for early locating diagnosis of malignant trophoblastic cell disease. Methods:Three cell groups were included in the study: (1) choriocarcinoma cells (poorly differentiated) (JAR, n=10), (2) early gestational trophoblastic cells (ETC, n=10) and (3) late pla...     

Optimal Use of BRAF Targeting Therapy in the Immunotherapy Era

Purpose of Review

The therapeutic landscape for metastatic melanoma has been revolutionized in recent years. This review will discuss existing evidence for therapeutic approaches for BRAF-mutated metastatic melanoma.

Recent Findings

Clinical trials involving combined BRAF/MEK inhibition with either vemurafenib plus cobimetinib or dabrafenib plus trametinib have shown improved overall survival compared to monotherapy with BRAF inhibitors alone. In a subset of patients with good prognostic factors, long-term clinical benefit has been noted. Simultaneously, developments in immunotherapy have suggested long-lasting survival for some patients.

Summary

In advanced BRAF-mutated melanoma, both BRAF/MEK inhibition and immunotherapy agents show improved overall survival and, in a small population of patients, prolonged and long-term benefit as compared to standard chemotherapy. Trials are currently underway evaluating sequencing of these therapies and the safety of targeted therapy plus immunotherapy combinations.

     

Rare <Emphasis Type="Italic">RAS</Emphasis> Mutations in Metastatic Colorectal Cancer Detected During Routine <Emphasis Type="Italic">RAS</Emphasis> Genotyping Using Next Generation Sequencing

Background

Overall survival of metastatic colorectal cancer (mCRC) patients has been improved with the addition of targeted therapy such as anti-epithelial growth factor receptor monoclonal antibodies (anti-EGFR mAbs) to standard chemotherapy. Retrospective studies and randomized trials showed that the presence of RAS mutations was linked to the absence of clinical response to anti-EGFR mAbs. Patients harboring KRAS and NRAS mutations on exons 2, 3 or 4 have little or no benefit from anti-EGFR therapies. Polymerase chain reaction (PCR)-based assays are routinely used to assess KRAS and NRAS status, whereas deep sequencing with next generation sequencing (NGS) currently represents an alternative method.

Objective

The objective of our study was to identify KRAS and NRAS non-hotspot mutations using NGS of mCRC tumor samples.

Method

DNA was extracted from 188 consecutive formalin-fixed paraffin embedded samples of histologically proven colorectal cancer tumor tissue from patients with mCRC. Following amplification, DNA was sequenced by ultra-deep pyrosequencing. Non-hotspot mutations identified by NGS (frequency of mutated allele range [1.8–70.6 %]) were confirmed by Sanger direct-sequencing when possible.

Results

NGS procedure was applicable in 94 % of the cases and detected mutations in 62 % of the samples. Nine uncommon mutational profiles were found with a frequency of mutated allele ?>?1 %. Silent mutations were found in 3.6 % of the samples. Mutations at or near functional domains of RAS proteins, other than defined hotspots, were found in 3.6 %. NGS proved to be accurate, sensitive and suitable for routine RAS genotyping.

Conclusion

Clinical responses to anti-EGFR mAbs are potentially impaired in the presence of these uncommon RAS mutations.

     

Insights Into the Relationship Between Gut Microbiota and Colorectal Cancer

Purpose of review

There is growing evidence to suggest that gut microbiota plays an important role in colorectal carcinogenesis. Western diet is associated with gut microbial dysbiosis, which leads to inflammation, oxidative stress, and genotoxic effects, all common risk factors for colorectal cancer.

Recent findings

Fusobacterium nucleatum, Helicobacter pylori, Bacteroides fragilis, Escherichia coli, and Streptococcus bovis are the main bacterial species associated with colorectal carcinogenesis. Gut microbiota transforms both diet- (meat, processed meat products, fat) and host (bile acids)-derived precursors into carcinogens and further interferes with anti-cancer drug metabolism, chemotherapy efficacy, and drug-induced toxicity. Nutritional interventions, as well as the administration of beneficial bacteria (probiotics), dietary fiber (including prebiotics) supplements, and synbiotics (probiotic + prebiotic), may reduce the risk of colorectal cancer and side effects of anti-cancer therapy.

Summary

Current evidence suggests gut microbiota may predispose or protect against colorectal cancer. Restoring gut microbial dysbiosis is an emerging nutritional and clinical target in oncology.

     

Targeted Next-Generation Sequencing in Men with Metastatic Prostate Cancer: a Pilot Study

Introduction

Tumor profiling by targeted next-generation sequencing (tNGS) and personalized treatment based on these results is becoming increasingly common in patients with metastatic solid tumors, but it remains unclear whether this strategy results in benefit to patients with metastatic prostate cancer (mPCa).

Objective

To assess the clinical utility of tNGS in treatment decision-making for patients with mPCa.

Patients and Methods

Patients with available genomic profiling using tumor tissue (FoundationOne, F1) or cell-free DNA (FoundationACT, Guardant360) were included. Targetable genomic alterations (tGA) included a change in the copy number or mutations in DNA repair genes, mismatch repair genes, PTEN, cyclin-dependent kinases, ERBB2, BRAF, TSC, and the PIK3/mTOR pathway.

Results

The study included 66 patients, 86% of which had metastatic castration-resistant prostate cancer (mCRPC), and who had received a median of 3 (range 0–7) treatments prior to tNGS. The most frequent alterations were found in TP53 (42%), PTEN (35%), androgen receptor (AR) (30%), DNA repair (30%), PIK3CA signaling pathway (21%), cyclin-dependent kinases (15%), BRAF (9%), and MMR/MSI (6%) genes. Among the 45 (68%) tGA+ patients, tNGS influenced treatment in 13 (29%) [PARP inhibitor (n?=?7), mTOR inhibitor (n?=?4), anti-PD-1 (n?=?2), anti-HER2 (n?=?1)]. The median progression-free survival (PFS) was 4.1 months [95% confidence interval (CI), 2.8–5.4]. Among tGA+ patients who did not receive tNGS-based therapy, systemic treatment (n?=?17) included chemotherapy (71%), new generation anti-androgen therapy (24%), and cabozantinib (6%); the median PFS was 4.3 months (95% CI, 2.6–6.0; p?=?0.7 for tGA+ with personalized therapy vs. tGA+ without personalized therapy).

Conclusion

In this cohort, the use of tNGS was feasible, detected frequent genomic alterations, and was used late in the disease course. Further studies and larger portfolios of targeted therapy trials are needed to maximize the benefit of tNGS in this population.

     

Targeting thiamine-dependent enzymes for metabolic therapies in oral squamous cell carcinoma?

Purpose

Thiamine-dependent enzymes (TDEs) linking glycolysis with the tricarboxylic acid cycle (TCA) pyruvate dehydrogenase (PDH), of the pentose phosphate pathway transketolases (TKTs), the TCA alpha-ketoglutarate deydrogenase (KGDH)/2-oxoglutarate dehydrogenase (OGDH) complex, and the amino acid catabolism branched-chain alpha-ketoacid dehydrogenase (BCKDH) complex are crucial factors for tumor metabolism. The expression of these enzymes has not been analyzed for carcinogenesis of oral squamous cell carcinoma (OSCC) with special focus on new targeted metabolic therapies as yet.

Methods

TDEs PDH, KGDH (OGDH), and BCKDH were analyzed in normal oral mucosa (n = 14), oral precursor lesions (simple hyperplasia, n = 21; squamous intraepithelial neoplasia, SIN I–III, n = 35), and OSCC specimen (n = 46) by immunohistochemistry and western blot (WB) analysis in OSCC tumor cell lines.

Results

Although the total numbers of PDH and KGDH (OGDH) positive samples decreased in OSCC, both enzymes were significantly overexpressed in the carcinogenesis of OSCC compared with normal tissue. BCKDH has been demonstrated to be significantly overexpressed in the carcinogenesis of OSCC. Specificity of the antibodies was confirmed by WB analysis.

Conclusions

This is the first study showing increased expression of TDEs in OSCC. Metabolic targeting of TDEs (including TKTs) by antagonistic compounds like oxythiamine or oxybenfothiamine may be a useful strategy to sensitize cancer cells to common OSCC cancer therapies.