Molecular Imaging Theme 1 Accomplishments

Molecular Imaging Theme 1 Accomplishments

To assess the potential role of cathepsin B in premalignant progression of breast epithelial cells, program members employed a 3D reconstituted basement membrane overlay culture model of MCF10A human

breast epithelial cells and premalignant variants and imaged their development. They found that CA074Me, a cell-permeable inhibitor selective for the cysteine cathepsins B and L, reduced proliferation and increased apoptosis.  These findings are consistent with studies by others showing that deletion of cathepsin B in the transgenic MMTV-PyMT mice, a murine model that is predisposed to development of mammary cancer, reduces malignant progression.  The 3D/4D models are being used to identify novel druggable targets in triple negative breast cancers and during the transition from ductal carcinoma in situ to invasive ductal carcinoma. Dr. Sloane recently was awarded an R21 to develop dynamic 3D/4D microfluidic models modeling cellular interactions in the lymphatic metastasis of breast cancer.

• Lead Investigators - Drs. Sloane and Moin

Program members have developed α-methyl-L-tryptophan (AMT) to assess the tryptophan pathway using PET imaging in various cancers.  In brain tumors, the group has found AMT-PET to be highly sensitive for detecting gliomas and glio-neuronal tumors. They have also observed AMT accumulation in human meningiomas and brain metastases. In the course of the study, they observed AMT accumulation in glioma-infiltrated brain tissue an important, but often missed, target for resective surgery and post-surgical radiation.  Kinetic analysis of tumoral AMT uptake was also able to differentiate low-grade astrocytomas from oligodendrogliomas. Tumoral net transport rates of tryptophan showed a high predictive value for the proliferative activity. In addition, AMT-PET proved to be highly accurate to differentiate glioma recurrence from radiation injury.  Recent studies of the group have also demonstrated the strong, independent prognostic value of post-treatment AMT-uptake for survival of patients with high-grade glioma. AMT-PET imaging has been also extended to lung and breast cancers to obtain pilot data on extracranial tumors that commonly metastasize into brain. The results indicated different AMT kinetics in the primary tumors, suggesting that drugs targeting tumoral tryptophan metabolism may be differentially effective in these tumors. In tissue-imaging comparisons, high AMT metabolic rates found in gliomas and meningiomas with high IDO expression suggested AMT-PET as a potential imaging approach for monitoring treatment response to IDO inhibitors targeting tumoral immune resistance.  This also facilitated extending AMT imaging to IDO-expressing extracranial tumors.  They found high tumoral expression of the L-type amino acid transporter in most gliomas and breast cancers, suggesting that variability in LAT1 expression is unlikely to explain variations in in vivo tracer uptake.  Based on this, AMT appears to be a unique amino acid tracer (as compared to other amino acid tracers used for cancer imaging) to study and monitor tumoral immune resistance mediated by abnormal tryptophan metabolism via the kynurenine pathway.

• Lead researcher -  Dr. Juhász
• Collaborative researchers - Drs. Alkonyi, Batista, Kamson, Christensen and Zitron

Program members are developing new PET tracers for the assessment of a number of pathways activated in cancer. The growth factor receptors (GFRs) - PI3K/AKT/mTOR pathway is frequently altered in cancer and a number of therapeutic agents have been developed and are being tested to block this pathway as part of cancer treatment. Activating mutations in EGFR kinase in NSCLC that respond to therapy with EGFR kinase inhibitors (i.e., erlotinib) can be non-invasively imaged using a new PET imaging agent 18F-PEG6-IPQA {4-[(3-iodophenyl)amino]-7-(2-[2-{2-(2-[2-{2-(18F-fluoroethoxy)-ethoxy}-ethoxy]-ethoxy)-ethoxy}-ethoxy]-quinazoline-6-yl-acrylamide)} and derivatives, developed by program members. Also, the team has been developing novel agents for early detection of pancreatic and hepatocellular carcinomas via expression of HIP/PAP protein (aka, lactose-binding protein). Currently, the group is collaborating with members of the Tumor Biology and Microenvironment program on the development of a novel PET and fluorescence imaging agent targeted to galectin-3 (Gal-3) that is highly expressed on several different carcinomas, including pancreatic, hepatocellular, prostate, breast, etc.

• Lead researcher - Dr. Gelovani
• Collarborative researchers -  Drs. Pal, Raz, Tian, Turkman and Yeh

The synthesis of radiolabeled 17β-hydroxy-16α-[131I]iodo-wortmannin, as a potential PET tracer for PI3K and radiolabeled imatinib analogs as potential agents for PET imaging of Bcr-Abl and c-KIT expression at a kinase level was developed by program members. Using these molecular imaging agents in patients may be useful for the assessment of mutant growth factor pathway activation and/or treatment-inducted inhibition.  Epigenetic modifications mediated by histone deacetylases (HDACs) also play important roles in both cancer and neurologic diseases and HDAC inhibitors, such as vorinostat, and are being used in the treatment of cancer.  6-([18F]fluoroacetamido)-1-hexanoicanilide (18F-FAHA) is being developed by the team for use with PET and it reflects the level of expression-activity of HDAC class IIa enzymes in the brain and other organs and tissues.  Furthermore, PET/CT/MRI with 18F-FAHA enabled non-invasive, quantitative assessment of pharmacodynamics of the HDAC inhibitor SAHA in the brain and will be applicable to use in the monitoring of cancer treatment with these inhibitors.  Together with colleagues at the Arizona Cancer Center, the group has been developing and testing novel internalizing phage (iPhage) libraries for targeting mammalian cellular organelles for research and therapeutic purposes (Rangel R, Nat Protoc. 2013).

• Lead researcher - Dr. Gelovani
• Collaborative researchers - Drs. Arab, Pasqualini, Peng, Rangel Sun and Yeh

The development of new MRI methods is also an important goal of the Program. Program members are developing new agents to improve and expand the utility of MRI and are collaborating with members fo the Molecular Therapeutics research program in these efforts. They are synthesizing a variety of new contrast agents including lanthanide(III)-containing polyaminopolycarboxylate-type complexes using polyethylene glycol that can be fine-tuned to modulate water exchange. This can potentially improve the contrast obtained with MRI compared to the standard contrast agents (Siriwardena-Mahanama BN, Dalton Trans, 2013). The team also developed a series of Eu(2+)-containing cryptates and studied the affect of different magnetic field strengths, temperatures, and pH values. These contrast agents may be particularly useful at high field strengths (e.g. 7T) which are now being evaluated. Initial in vivo studies have been promising. Additionally, the tunable oxidation offered by the combination of new ligands and the Eu(2+) ion offer the potential for imaging oxidation events. Towards this goal, program members encapsulated his complexes in liposomes and demonstrated the ability to detect oxidation with MRI regardless of the concentration of the contrast agent (manuscript submitted). They have also synthesized pH-responsive, dimetallic Eu(III)-containing complexes for MRI which exhibit a luminescence-decay rate which decreases with increasing pH over a biologically relevant range of 4-8. Low tumor pH is an important marker of cancer that is associated with the development of cancer and may also be linked to tumor aggressiveness and resistance to chemotherapy. Modulation of the luminescence-decay rate is independent from the concentration of Eu(III), and is expected to be useful in the non-invasive imaging of in vivo pH. While others are working on PET and hyperpolarized MR approaches to measure tumor pH, the use of a simple contrast agent would be simpler.

• Lead researcher - Dr. Allen
• Collaborative researchers -  Drs. Cisneros, Garcia, Haacke, Moore, Siriwardena-Mahanama