Mohanad Mossalam, PhD

Postdoctoral Fellow

Department of Pharmaceutics & Pharmaceutical Chemistry

421 Wakara Way, Rm 306
Salt Lake City
Utah, 84108
ph: 801.581.7120

Research Projects

Subcellular Targeting: Delivering Therapeutics to the Next Level.

The tumor suppressor p53 is mislocalized or mutated in inflammatory breast carcinoma. Its nuclear accumulation is essential for its transcriptional activities leading to induction of proteins involved in both the intrinsic and extrinsic apoptotic pathways. In addition, p53 triggers a non-transcriptionally mediated intrinsic apoptotic response if delivered to the mitochondria. This broadly accepted paradigm of p53 function supports the development of therapeutics involving restoration of the lost p53 function in the tumors, leading to growth inhibition of cancer cells.

I’m working on investigating an improved mechanism for p53 cancer therapy by utilizing a novel dual gene therapy—employing simultaneous nuclear and mitochondrial targeting of p53– to achieve therapeutically relevant apoptosis in breast cancer cells. First, to target p53 to the nucleus, a p53 “protein switch” will exploit our emerging technology where ligand induction leads to nuclear accumulation of the target protein. Second, p53 directed to the mitochondria with a mitochondrial targeting signal (MTS) will have intrinsic apoptotic activity but improved activity will be achieved by increasing mitochondrial localization (by selection of an optimal MTS, mutation of the nuclear localization signals in p53, and introduction of a mutation in the proline rich domain that increases mitochondrial-mediated apoptosis).

Inflammatory breast carcinoma (IBC), a particularly aggressive and deadly form of breast cancer with a higher occurrence of metastases, has mislocalized or mutated p53 and therefore should readily respond to this type of therapy.

In Summary:

1.      Demonstrate that localization controllable versions of p53 with nuclear localization signal (NLS) will translocate to the nucleus upon ligand addition causing apoptosis in MCF-7 breast cancer cells.

2.      Enhance mitochondrial targeting of p53 engineered with an improved mitochondrial signal and by introducing mutations in the nuclear localization signals and the proline rich domain.

3.      Simultaneous targeting of p53 to the nucleus and mitochondria will induce apoptosis in breast cancer cells, resulting in increased potency compared to the action of either construct alone.