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Dr. Susann Brady-Kalnay is an expert on cell adhesion molecules in cancer progression, with an emphasis on studying the disregulation of the molecule PTPmu (PTPRM) in brain tumors and other cancers. The Brady-Kalnay Lab is developing platform technologies exploiting their insight into cell adhesion molecule dysfunction in cancer to develop specific molecular imaging agents and novel targeted therapeutics.

Cell Adhesion Molecule Proteolysis is a Key Step in the Loss of Contact Inhibition of Growth and Movement in Cancer

We recently established the existence of a key change in proteolysis of the Receptor Protein Tyrosine Phosphatase PTPmu in human cancer: full length PTPmu protein expression is reduced in aggressive invasive and metastatic tumors due to proteolysis. This includes the high-grade brain tumor, glioblastoma multiforme (GBM). We observed proteolyzed fragments of PTPmu both outside and inside of tumor cells. These fragments have unique signaling features and contribute to the growth and invasiveness of tumor cells. Based on these findings, we proposed that cell adhesion molecule proteolysis is a key step in the loss of contact inhibition of growth and movement observed in cancer cells.

A Platform Technology to See(k) and Destroy Cancer Cells

By applying over three decades worth of Dr. Brady-Kalnay’s research on the Ig superfamily, PTPmu mediated cell adhesion in normal cells, and the study of its proteolysis in cancer cells, we designed peptides that bind to the PTPmu fragments but not the normal protein to specifically detect and image cancer.  The most effective peptide for identifying individual cancer cells was SBK2. By conjugating the same peptides to fluorophores, metals, or radioactive isotopes, we created a platform technology that can be used to recognize cancer cells in applications that range from diagnosis to imaging to the targeted treatment of primary, invasive and metastatic tumors to “see(k) and destroy” cancer by creating a new class of visual therapeutics. 

Fluorescence Optical Imaging

The ability to image tumors and their invasive edges or boundaries in real time during surgery is of vital importance for effective surgical management of cancer. Yet brain tumors are difficult to image because of the invasive nature of the cancer cells - they migrate away from the main tumor mass in clusters of cells that can’t be seen with either the naked eye or microscopically with white light reflectance. In the laboratory, we have used many innovative imaging tools, including 3-dimensional cryo-image analysis system to visualize nerves, blood vessels, and individual invasive cancer cells in brain tumor models.  Based on PTPmu proteolysis, the Brady-Kalnay laboratory developed a set of optical imaging agents to the PTPmu biomarker to visualize tumor cells in vivo. The fluorescent PTPmu agents bind to invading/dispersing cancer cells in models of many tumor types. We are pioneering the use of the fluorescent PTPmu imaging agent for image-guided surgical resection of tumors.  The fluorescence-guided surgical technique is currently receiving significant clinical attention given its potential for high level of effectiveness in improving the extent of surgical resection and thus prolonging survival outcomes for cancer patients. 

Magnetic Resonance Imaging (MRI)

MRI is an ideal modality for high-resolution tumor imaging and is standard of care for diagnosis and monitoring of treatment especially in brain tumors. This is accomplished by IV administration of a non-specific contrast agent gadolinium (Gd) that enhances areas of large tumor masses where the blood brain barrier is disrupted. This non-specific contrast only labels the center of the primary tumor and is not capable of enhancing the full extent of the tumor including the invasive regions. By conjugating the SBK2 peptide to a chelator, we created an efficient, selectable means to convert the peptide to an MRI imaging agent. This is achieved by complexing an enhancing metal like Gd into the chelator. We demonstrated that the PTPmu (SBK2)-Gd molecular MRI agent can identify a brain tumor lesion more specifically and with higher and more sustained contrast than conventional contrast agents. We are collaborating with the MRI group at �ǿմ�ý to improve molecular imaging further by using various MRI acquisition techniques including magnetic resonance fingerprinting (MRF) and quantitative MRI. 

Positron Emission Tomography (PET) and Radiotherapy 

By switching the Gd in the SBK2-chelator for a radioisotope, we create an agent for use in PET imaging. PET has advantages over MRI in many cancer applications, and generally has better sensitivity than MRI. Furthermore, the SBK2 agent can be complexed with an alpha or beta emitting high energy isotopes to deliver a lethal amount of ionizing radiation directly to cancer cells and their immunosuppressive tumor microenvironment.

Novel Therapeutics

Extracellular Modulators

Once again, by exploiting the process of PTPmu proteolysis, we have developed modulators of the cleaved extracellular fragment. The MAM, Ig, and first two FNIII repeats of the PTPmu extracellular domain are necessary for mediating homophilic adhesion between two PTPmu molecules on different cells in trans. This association is hypothesized to be necessary for the proper structuring of cell-cell junctions. Proteolysis of PTPmu results in the generation of the adhesive extracellular fragment and displacement of the catalytically active intracellular domain. We hypothesize that proteolysis of RPTPs is a way for tumor cells to release cell-cell adhesion thereby ensuring invasive and metastatic success. By generating modulators to the PTPmu extracellular domain, we expect to alter the invasive nature of tumor cells.

Intracellular Therapeutics

When full-length PTPmu protein is proteolyzed to yield the extracellular fragment, a cytoplasmic intracellular domain capable of translocating to the nucleus is also produced.  Human brain tumors retain the expression of the intracellular fragments. Phosphatase activity of the fragments is important in promoting migration, as inhibition of PTPmu phosphatase activity using a peptide inhibitor targeting the helix-loop helix wedge motif in the intracellular domain of PTPmu blocked tumor cell migration in vitro. In addition, PTPmu intracellular fragments are required for tumor cell survival in vitro, as use of shRNA targeting the intracellular domain reduces tumor cell survival. Finally, we determined that inhibition of PTPmu fragment expression in human cancer cells reduces tumor growth in vivo.  As a result of these studies, we developed inhibitors directed to the intracellular domain of PTPmu as novel cancer therapeutic agents.