To date, there are no approved targeted therapies for malignant small cell lung cancer (SCLC), due to no treatment advances in 30 years. However, Two novel researches lay the foundation for future research and have the potential to advance treatments for this highly malignant cancer.

A study, entitled with “RET Mutation and Expression in Small Cell Lung Cancer,” was published in the journal Thoracic Oncology and found a new mutation in SCLC which may play a role in the disease development. The researchers found that the genetic mutation, called RET (rearranged during transfection), was linked to rapid cell growth.

The other study, published in PLOS One, outlines a novel approach to identify new drug therapies for SCLC based on tumors’ genomic profiles. The research team discovered new molecular targets for treating the disease by extracting data from SCLC tumors to examine drug sensitivity. Through this analysis, they outlined a promising new approach to predict which cancer-fighting drugs would be the most broadly effective at slowing tumor growth.

The two studies enabled us to identify which molecules are implicated in driver mutation and which drugs may be the most useful in which types of tumors. Small cell lung cancer is one of the fastest growing cancers and these studies have yielded small but important therapeutic insights into this disease.

References:

1. RET Mutation and Expression in Small-Cell Lung Cancer. Journal of Thoracic Oncology, 2014; 9 (9): 1316

2. Genomic characterisation of small cell lung cancer patient-derived xenografts generated from endobronchial ultrasound-guided transbronchial needle aspiration specimens. PLoS One. 2014 Sep 5;9(9):e106862.

A recently published research reports that investigators have developed a novel strategy for reducing the often serious side effects of an important class of modern anticancer drugs — tyrosine kinase inhibitors. The novel drug is supposed to restrict its activity with high selectivity to the malignant tumor.

Severe side effect is one of biggest problems in modern cancer therapy, and ultimately leads to treatment having to be stopped. Targeted cancer drug is based on the specific inhibition of proteins that are over-activated in cancer cells and which drive abnormal cell growth. However, clinical practice has shown that, as a result of the physiological functions of these proteins in healthy tissue, their inhibition can cause severe side effects.

Facing such challenge, scientists have been successfully synthesized a new inhibitor that is coordinated to cobalt(III). This leads to initial drug inactivation and, thus, no activity under normal physiological conditions. Only in tumour tissue where low-oxygen conditions unusually prevail, the inactive cobalt(III) compound is reduced to cobalt(II) and as a result releases the active drug. The tumour-selective effectiveness of this approach has been demonstrated both in living cells and in tumor-bearing organisms.

So far, there has been no comparable strategy for reducing the (severe) side effects of tyrosine kinase inhibitors. As a result, there is hope that, in future, the approach presented here will improve the tolerance of the therapy and allow this treatment to benefit patients who have previously had to discontinue it.

Reference:

Tumor-Targeting of EGFR Inhibitors by Hypoxia-Mediated Activation. Angewandte Chemie International Edition, 2014;

Researchers from Ottawa and Taiwan have demonstrated a new insight into the common existence of chemoresistance in women ovarian cancer and provided a new possibility in its diagnosis and treatment. Their study was published in PNAS.

According to related data, about 2700 Canadian women were diagnosed ovarian cancer in 2014 and 1750 of them died. The ovarian cancer was always diagnosed in the terminal stage, and chemoresistance has already shown up at the time. Chemoresistance is a major hurdle in cancer treatment. Down-regulation of apoptosis pathways in one of the key determinants for chemoresistance.

In this study, researchers have tested the hypothesis that gelsolin (GSN) plays an important role in gynecological chemoressistance. They have provided strong evidence in support of GSN as an important etiologic factor in chemoresistance in vitro and determined the mechanism by which GSN exerts its prosurvival action. The findings also suggest that the application for C-terminal GSN may represent a new therapeutic strategy for chemoresistance gynecologic cancer. The in vitro findings have been validated with a clinical investigation that determines the relationship between GSN expression and cis-Diammine dichloroplatinium (Ⅱ) sensitivity in human ovarian tumor.

These findings agree with the notion that GSN plays a key role in the regulation of gynecological cell fate as reflected in chemoresistance.

Reference:

Chong P S Y, Zhou J, Cheong L L, et al. LEO1 Is Regulated by PRL-3 and Mediates Its Oncogenic Properties in Acute Myelogenous Leukemia[J]. Cancer research, 2014, 74(11): 3043-3053.

Scientists from National University of Singapore have found the overexpression of Leo1 gene will significantly influence other genes which have directly relations with Acute Myelogenous leukemia(AML), then enhance the incidence of cancer. Through inhibiting Leo1 and its downstream signaling pathway, this study, published in Cancer Research, potentially provides a new regimen for AML patients.

PRL-3 is a small dual specificity phosphatase and has been shown to promote cellular processes, such as cell motility, invasion and survival. PRL-3 was first linked to cancer when it was consistently found at elevated levels in colorectal cancer metastases, but at much lower levels in matched early-staged tumor and normal colorectal epithelium. Stable expression of PRL-3 confers cytokine independence and growth advantage of AML. However, how PRL-3 mediates these functions in AML is still unknown.

In this study, researchers have indicated that Leo1, a component of RNA polymerase -associated factor(PAE) complex, is a novel and important mediator of PRL-3 oncogenic activities in AML. They have described a novel mechanism where elevated PRL-3 protein increases JMJD2C histone demethylase occupancy on Leo1 promoter, thereby reducing the H3K9me3 repressive signals and promoting Leo1 gene expression. Inhibition of Leo1 reverses PRL-3 oncogenic phenotypes in AML. Loss of Leo1 leads to destabilization of PAF complex and downregulation of SOX2 and SOX4, potent oncogenes in myeloid transformation.

This finding has implicated a pro-oncogenic role of PRL-3 in AML, and reveals Leo1 as a novel downstream molecule required for PRL-3 oncogenic function in leukemia.

A research from C Denoyelle and B Lambert reports that EGFR inhibitor and the BH3-mimetic molecule ABT-737 synergize in the killing of ovarian cancer cell lines.

They wondered whether the association of an anti-EGFR monoclonal antibody (cetuximab) or EGFR TKIs (erlotinib and gefitinib) with a BH3-mimetic molecule (ABT-737), which binds and neutralizes BCL-X_L, could have the same effect as miR-491-5p. Indeed, the combination of these different EGFR inhibitors with ABT-737 (or siRNA-BCL-X_L) induced apoptosis in IGROV1-R10 cells, whereas each drug alone had no obvious effect.

Moreover, they observed that this combination could be also effective in the ovarian cancer cell line OVCAR-3. Indeed, whereas ABT-737 induced a mild apoptosis, the combination of EGFR TKI (erlotinib or gefitinib) with a BH3-mimetic molecule led to a massive apoptosis in OVCAR-3 cells .

Altogether, these observations highlight the interest in pursuing a combination therapy of an EGFR inhibitor with a BH3-mimetic molecule in ovarian cancer. Finally, as expected with our previous results obtained with miR-491-5p, the combination of cetuximab (or erlotinib or gefitinib) and ABT-737 (or siRNA-BCL-X_L) did not induce cell death in SKOV3 cells.

A research from C Geismann and F Grohmann shows that c-Rel is a critical mediator of NF-κB-dependent TRAIL resistance of pancreatic cancer cells.

 In their cell-based models of Pancreatic ductal adenocarcinoma (PDAC), they were able to show for the first time that c-Rel is a central mediator of an antiapoptotic signalling pathway protecting from TRAIL-induced apoptosis. By siRNA-mediated downregulation of c-Rel expression, they were able to show that c-Rel is part of the NF-κB complex induced by TRAIL and conferring apoptosis resistance to an extent similar to other NF-κB family members.

As initially shown by array analysis and later confirmed by qPCR and EMSA, c-Rel induces the expression of the transcription factor NFATc2 in TRAIL-resistant PDAC cell lines. SiRNA-mediated downregulation of either c-Rel or NFATc2 significantly sensitized PDAC cell lines to TRAIL-induced apoptosis and abolished the induction of COX-2 expression by TRAIL in these cell lines. In line with this, pharmacologic inhibition of COX-2 by celecoxib greatly sensitized the PDAC cell lines in an extent similar to c-Rel or NFATc2 inhibition.

Notably, unlike a recent study showing comparable effects of c-Rel on the apoptotic response in head and neck cancer, they did not observe any changes in proapoptotic genes such as PUMA or p21 in the array analysis. In contrast to reports indicating a proapoptotic function of c-Rel, they clearly established an antiapoptotic effect of c-Rel in TRAIL-resistant PDAC cell lines.