Research

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

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.

Identification of Non-Coding RNAs Involved in Metastasis

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 suppressors 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.

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

MicroRNA 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.

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

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.

Research Support

CA160445 Ajani (Contact PI, Calin Partnering PI) 09/30/2017 – 09/29/2020
Department of Defense (DoD)
Discover Novel Therapeutic Strategies for Peritoneal Metastases From Gastric Adenocarcinoma
To identify novel therapeutic targets for gastric adenocarcinoma patients with peritoneal carcinomatosis.

R01 CA222007-01A1 Calin (corresponding MPI) 08/01/2018 - 07/31/2023
NIH/NCI
miR-155 targeted therapeutics for precision medicine in lung cancer
Perform preclinical safety and toxicity studies to test the efficacy and safety of adjuvant anit-miR-155 therapies, coupled with SLNP-anti-miR-155 or AXL-Apt-SLNP-anti-miR-155, alone or in combination with cisplatin and vinorelbine.

R01 GM122775-01A1 Calin (corresponding MPI) 09/01/2018 - 08/31/2021
NIH/NCI
Viral miRs and cellular miRs in sepsis
Focus on identifying expression signatures of host/cellular- and xeno/viral-miRNAs, their role in predicting the risk for septic shock, and to use the acquired knowledge to develop new therapeutic agents for sepsis.

R01CA211044 - Rezvani (PI) 12/20/2016 - 11/30/2021
NIH/NCI
Off-the-shelf engineered NK cells for the treatment of AML
Goal: The long-term objective of this research is to develop novel cell based therapies to harness the antileukemic potential of NK cells against AML, and to further enhance their effector function by both redefining their specificity and/or enhancing their potency.

CLL Global Research Foundation#1 (Calin PI) 11/1/2019-10/31/20
RNA to DNA variations in the CLL genome
We plan to study the critical role of DRAIs and CCAT2 in the evolution of CLL from an indolent disease to the very aggressive CLL non-responsive to therapy and the Richter transformation.

CLL Global Research Foundation#2 (Calin PI) 04/1/2020-03/31/21
Plasma miRNAs as predictors of second cancer risk in patients with CLL
We propose the use of circulating microRNAs as diagnostic and prognostic biomarkers for risk in the patients with the most frequent type of leukemia, the chronic lymphocytic leukemia (CLL) to develop the most frequent type of secondary cancers unrelated to therapy, the skin cancers.