Current Research

Identification of the Roles of microRNAs and 
Other Non-Coding RNAs in Cancer Predisposition

Hypothesis

Familial cancers represent diseases in which non-coding RNAs have central pathogenetic roles. We hypothesize that previously non-identified, non-coding RNAs with roles in sporadic and familial cancers could be identified by using their genomic association (flagging) with known cancer-associated, single-nucleotide polymorphisms (SNPs). Furthermore, SNPs in interactor sites with microRNAs are involved in cancer predisposition. The genome-wide identification of non-coding RNAs predisposed to cancer would prove a new mechanism of cancer predisposition with clear implications for further molecular screening and diagnosis.

ncRNAs in Familial Cancers

Identification of Non-Coding RNAs Involved in Metastasis

Hypothesis

During tumorigenesis, genome-wide abnormalities in both microRNAs and ultraconserved genes (UCGs) occur in a correlated way that results in our hypothesis that dramatic differences occur in the expression of UCGs and miRNAs in non-metastatic versus metastatic cancers. microRNAs have important genes as targets – including known oncogenes and tumor supressors involved in pancreatic invasion and metastasis. Additionally, miRNAs interact directly with and regulate the expression of UCGs and/or, conversely, UCGs can regulate the expression of miRNAs. The transcriptional or post-transcriptional down-regulation of target levels by miRNAs and UCGs may have functional consequences by impairing the cell cycle and the survival, migration and invasion capacity of cancer cells.

ncRNAs in Metastasis

Identification of microRNAs and Other Non-Coding RNAs as Diagnostic and Prognostic Markers in Human Cancers
microRNAs as the Oldest Hormones

Hypothesis

miRNA levels in the plasma from cancer patients are significantly different than those of non-cancer control individuals. The plasma miRNAs levels from cancer patients correlate with clinical and prognostic parameters and the miRNA quantification from plasma could be included as a new prognostic marker. Furthermore, the identification of traces of specific miRNAs, known to have a pathogenetic effect, could signal the recurrence of disease. Human-specific ncRNAs exist in the genome and are involved in the functional fingerprints that differentiate human cancers from cancers in other organisms. microRNAs are secreted by malignant cells in the microenvironment and uptake directly or through bodily fluids by effector cells.

microRNAs as the Oldest Hormones

Development of New Therapeutic Strategies Involving microRNAs and Other Non-Coding RNAs

Hypothesis

microRNAs could represent a new family of tumor suppressor or oncogenic targets for cancer gene therapy. The microRNA viral vectors will be released efficiently inside the target cells and induce or block the expression of microRNAs of interest. The microRNA viral vectors will induce apoptosis of malignant cells and the spectrum of altered targets will include protein-coding genes known to be important in human tumorigenesis.

microRNAs/ncRNAs as Therapeutic Strategies

 

Ongoing Research Support

1045-12-02  Calin (PI)
Leukemia and Lymphoma Society 07/01/2011-06/30/2016
Non-codingRNA network in Leukemias: functional and clinical significance
Goal: To obtain results for developing new ways of cancer gene therapy

UH3TR000943-01  Calin (MPI) 08/01/2015-07/31/2018
NIH/NCI
Novel extra cellular RNA-based combinatorial RNA inhibition therapy
Goal: To develop new strategies using combined miRNA and siRNA to maximize therapeutic benefit by affecting the production of exRNAs.

1R01CA182905-01  Calin (MPI) 06/01/2014-05/31/2019
NIH/NCI - Protein-coding and non-coding RNA biomarkers for early detection of CLL
Goal: Find interactor pairs of microRNAs and target PCGs with key roles in the onset of disease, understand their mechanisms of action, and use the acquired knowledge to develop new diagnostic and prognostic tools.

1R01CA164346-01A1  You (PI) 09/01/2012-08/31/2016
NIH/NCI
Characterization and Targeted Therapy of T-All deficient for PTEN and INK4A/ARF Goal: To determine the extent of ncRNAs’ involvement in ALL therapy resistance
Role: Co-Principal Investigator

Keating, Punkett and Wierda (PI) 09/01/2015-08/31/2016
UTMDACC CLL Moon Shot - Flagship 2: Emerging Genetic Opportunities
Goals:  1) Identify by using non-codingRNAs profiling patients who are at risk of RS early in the disease. 2)  Understand how the cellular and viral microRNAs affect the function of normal B cells and induces transformation; 3)  Understand the non-codingRNAs-based mechanisms of resistance to ibrutinib and FCR;
Role:  PI of Flagship 2

UH2TR000943-02 – Supplement   Calin (MPI) 06/01/2015-05/31/2016
NIH/NCI
Novel extra cellular RNA-based combinatorial RNA inhibition therapy
Goal:  Identify and establish functional validity of novel IncRNAs as exRNA cancer therapeutic lead candidates.

CA182905-01 – Supplement    Calin (MPI) 06/01/2015-05/31/2016
NIH/NCI
Protein-coding and non-coding RNA biomarkers for early detection of CLL
Goal:  Investigate the involvement of a novel group of non-coding RNAs, the transcribed ultraconserved regions or T-UCRs

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