• Models Research and Co-clinical Trials

Pandolfi's laboratory has been seminal at elucidating the molecular mechanisms and the genetics underlying the pathogenesis of leukemias, lymphomas and solid tumors as well as in modeling these cancers.

Dr. Pandolfi and colleagues have characterized the function of the fusion oncoproteins and the genes involved in the chromosomal translocations of acute promyelocytic leukemia (APL), as well as of major tumor suppressors such PTEN and p53 and novel proto-oncogenes such POKEMON.

The elucidation of the molecular basis underlying APL pathogenesis has led to the development of novel and effective therapeutic strategies. As a result of these efforts, APL is now considered a curable disease. Novel therapeutic concepts have emerged from this work that are currently been tested in clinical trials.

Video Update:

The full study is available by clicking the "Learn More" link below.

 

 

Despite advances in early diagnosis, more than 40,000 women still die of breast cancer every year in the USA. A major roadblock to successful treatment is metastasis, or the dissemination and growth of primary cancer cells at secondary sites. Novel therapeutic strategies are urgently needed, but necessarily require improved understanding of the molecular mechanisms of metastasis. Thus the Pandolfi Lab is studying an integrated signaling and epigenetic program network in the context of breast cancer metastases.

We recently demonstrated that microRNA miR-22 modulates the epigenetic cancer landscape and thereby triggers epithelial-mesenchymal transition (EMT), enhances stemness, and promotes breast cancer development and metastasis (Song et al., Cell (2013)). We now are testing the therapeutic potential of LNA-based targeting of miR-22 as a treatment modality.

Lung cancer remains the leading cause of cancer-related deaths in the United States, and draws a growing number of its victims from the ranks of non-smokers. So it is critical that investigators develop a deeper understanding of the genetic pathways perturbed in this often-fatal disease. A fundamental obstacle to lung cancer therapy is that the cancer is frequently diagnosed at advanced metastatic stage, in which treatment is disappointing.
 
The Pandolfi Lab recently uncovered a role in lung cancer for the family of proteins known as DOK (for “downstream of tyrosine kinase”). A series of in vivo experiments led by Dr. Alice Berger revealed that the proteins Dok-1, Dok-2, and Dok-3 were involved in lung cancer tumor suppression. As the DOK2 gene is located in one of the genomic regions most frequently deleted in human lung cancer, these findings corroborated its emergence as a lung tumor suppressor that opposes lung cancer. We are currently studying if rare Dok2 variants are associated with lung cancer susceptibility in the case-control studies. We expect the information we obtain from these studies will identify genetic variants that improve screening, diagnosis, and treatment of human lung cancer.

 

We have recently described a novel mode of gene regulation that is based on the competitive endogenous RNA (ceRNA) language. Protein-coding and non-coding ceRNAs can crosstalk by competing for shared microRNAs, which constitute the words of this ceRNA language. On the basis of this new theory, we are utilizing computational predictions and experimental validation to unravel extensive regulatory networks that impact the expression of prominent cancer genes, thus adding numerous novel players to the list of putative tumor suppressors and oncogenes. We are currently focused on the characterization of the ceRNA biological dimension in vivo, with specific focus on the ceRNA networks of the critical tumor suppressor PTEN and the proto-oncogene BRAF.