MicroRNA silencing for cancer therapy targeted to the tumour microenvironment.

MicroRNAs are short non-coding RNAs expressed in different tissue and cell types that suppress the expression of target genes. As such, microRNAs are critical cogs in numerous biological processes, and dysregulated microRNA expression is correlated with many human diseases. Certain microRNAs, called oncomiRs, play a causal role in the onset and maintenance of cancer when overexpressed. Tumours that depend on these microRNAs are said to display oncomiR addiction. Some of the most effective anticancer therapies target oncogenes such as EGFR and HER2; similarly, inhibition of oncomiRs using antisense oligomers (that is, antimiRs) is an evolving therapeutic strategy. However, the in vivo efficacy of current antimiR technologies is hindered by physiological and cellular barriers to delivery into targeted cells. Here we introduce a novel antimiR delivery platform that targets the acidic tumour microenvironment, evades systemic clearance by the liver, and facilitates cell entry via a non-endocytic pathway. We find that the attachment of peptide nucleic acid antimiRs to a peptide with a low pH-induced transmembrane structure (pHLIP) produces a novel construct that could target the tumour microenvironment, transport antimiRs across plasma membranes under acidic conditions such as those found in solid tumours (pH approximately 6), and effectively inhibit the miR-155 oncomiR in a mouse model of lymphoma. This study introduces a new model for using antimiRs as anti-cancer drugs, which can have broad impacts on the field of targeted drug delivery.

Nanoparticle-based therapy in an in vivo microRNA-155 (miR-155)-dependent mouse model of lymphoma.

MicroRNA-155 (miR-155) is an oncogenic microRNA that regulates several pathways involved in cell division and immunoregulation. It is overexpressed in numerous cancers, is often correlated with poor prognosis, and is thus a key target for future therapies. In this work we show that overexpression of miR-155 in lymphoid tissues results in disseminated lymphoma characterized by a clonal, transplantable pre-B-cell population of neoplastic lymphocytes. Withdrawal of miR-155 in mice with established disease results in rapid regression of lymphadenopathy, in part because of apoptosis of the malignant lymphocytes, demonstrating that these tumors are dependent on miR-155 expression. We show that systemic delivery of antisense peptide nucleic acids encapsulated in unique polymer nanoparticles inhibits miR-155 and slows the growth of these "addicted" pre-B-cell tumors in vivo, suggesting a promising therapeutic option for lymphoma/leukemia.

Organization for rare diseases India (ORDI) - addressing the challenges and opportunities for the Indian rare diseases' community.

In order to address the unmet needs and create opportunities that benefit patients with rare disease in India, a group of volunteers created a not-for-profit organization named Organization for Rare Diseases India (ORDI; www.ordindia.org). ORDI plans to represent the collective voice and advocate the needs of patients with rare diseases and other stakeholders in India. The ORDI team members come from diverse backgrounds such as genetics, molecular diagnostics, drug development, bioinformatics, communications, information technology, patient advocacy and public service. ORDI builds on the lessons learned from numerous similar organizations in the USA, European Union and disease-specific rare disease foundations in India. In this review, we provide a background on the landscape of rare diseases and the organizations that are active in this area globally and in India. We discuss the unique challenges in tackling rare diseases in India, and highlight the unmet needs of the key stakeholders of rare diseases. Finally, we define the vision, mission, goals and objectives of ORDI, identify the key developments in the health care context in India and welcome community feedback and comments on our approach.

miRNA modulation of the cellular stress response.

Cellular stress responses are potent and dynamic, allowing cells to effectively counteract diverse stresses. These pathways are crucial not only for maintaining normal cellular homeostasis, but also for protecting cells from what would otherwise lead to their demise. A novel class of genes, termed miRNAs, has recently been implicated in the cellular stress response. For example, it has been demonstrated that a cardiac-specific miRNA that is not required for normal development is requisite for a normal cardiac stress response in mice. In addition, we have found that a miRNA family is able to modulate the cellular response to cytotoxic cancer treatment both in vitro and in vivo. In this review, we will discuss these and other important developments in the field. In particular, we will focus on studies that have linked miRNAs to the genotoxic stress response and will suggest how this connection may be both important for our understanding of biology and pertinent for the development of novel cancer therapies.

Inhibition of hypoxia-induced miR-155 radiosensitizes hypoxic lung cancer cells.

miR-155 is a prominent microRNA (miRNA) that regulates genes involved in immunity and cancer-related pathways. miR-155 is overexpressed in lung cancer, which correlates with poor patient prognosis. It is unclear how miR-155 becomes increased in lung cancers and how this increase contributes to reduced patient survival. Here, we show that hypoxic conditions induce miR-155 expression in lung cancer cells and trigger a corresponding decrease in a validated target, FOXO3A. Furthermore, we find that increased levels of miR-155 radioprotects lung cancer cells, while inhibition of miR-155 radiosensitizes these cells. Moreover, we reveal a therapeutically important link between miR-155 expression, hypoxia, and irradiation by demonstrating that anti-miR-155 molecules also sensitize hypoxic lung cancer cells to irradiation. Our study helps explain how miR-155 becomes elevated in lung cancers, which contain extensive hypoxic microenvironments, and demonstrates that inhibition of miR-155 may have important therapeutic potential as a means to radiosensitize hypoxic lung cancer cells.

Prevention of K-Ras- and Pten-mediated intravaginal tumors by treatment with camptothecin-loaded PLGA nanoparticles.

Primary squamous cell carcinoma of the vagina is an uncommon disease that often exhibits few symptoms before reaching an advanced stage. Topical intravaginal therapies for resolving precancerous and cancerous vaginal lesions have the potential to be non-invasive and safer alternatives to existing treatment options. Two factors limit the testing of this approach: lack of a preclinical intravaginal tumor model and absence of safe and effective topical delivery systems. In this study, we present both an inducible genetic model of vaginal squamous cell carcinoma in mice and a novel topical delivery system. Tumors were generated via activation of oncogenic K-Ras and inactivation of tumor suppressor Pten in LSL-K-RasG12D/+PtenloxP/loxP mice. This was accomplished by exposing the vaginal epithelium to a recombinant adenoviral vector expressing Cre recombinase (AdCre). As early as 3 weeks after AdCre exposure exophytic masses protruding from the vagina were observed; these were confirmed to be squamous cell carcinoma by histology. We utilized this model to investigate an anticancer therapy based on poly(lactic-co-glycolic acid) (PLGA) nanoparticles loaded with camptothecin (CPT); our earlier work has shown that PLGA nanoparticles can penetrate the vaginal epithelium and provide sustained CPT release. Particles were lavaged into the vaginal cavity of AdCre-infected mice. None of the mice receiving CPT nanoparticles developed tumors. These results demonstrate a novel topical strategy to resolve precancerous and cancerous lesions in the female reproductive tract.