Molecular Imaging Of Breast Cancer Research Articles

Molecular Targeting of Breast Cancer: Molecular Imaging and Therapy

Breast cancer is increasing at an alarming rate in women around the world, where medical biology is confronted by this disease on two crucial fronts. The first step is the early accurate diagnosis, which is very critical and the second step involves the appropriate clinical management. The current trend in molecular imaging of breast cancer provides not only an excellent tool in diagnosing the disease but also useful in validating the potentiality targeted of a pharmaceutical interventions. This review addresses the effectiveness of imaging technologies to resolve the molecular characterization and pathological evidences in breast cancer. The focus is on the present practices in breast cancer imaging, specifically targeting cellular machineries such as hormone receptors and angiogenic factors.

Abstract 4335: Imaging of cancer stem cells with radiolabeled Hedgehog

Abstract Recent studies have shown that the majority of early disseminated cancer cells detected in the bone marrow of breast cancer patients have a putative breast cancer “stem cell-like” phenotype. Moreover, activation of stem cell pathways in cancer cells has also been associated with resistance to radiation and chemotherapy. Early detection of these micrometastatic “stem cell-like” cancer cells could allow for earlier commencement of aggressive treatment to minimize relapse and disease spread and to improve therapeutic outcome. However, there is currently no stem cell targeted method to detect this population in vivo. New imaging agents are needed for real-time, non-invasive detection of stem cell pathway activation in micrometastatic disease in breast cancer. The stem cell pathway Hedgehog (HH) is known to regulate cell cycle entry and proliferation of embryonic neural and mammary progenitor cells as well as self-renewal of malignant mammary stem cells. Furthermore, the hedgehog receptor PTCH is overexpressed on cancer stem cells compared to normal mammary stem cells. Therefore, we sought to radiolabel the natural hedgehog ligand, sonic (SHH) with the positron emitter Gallium 68 (68Ga) for detection of cancer stem cells by positron emission tomography (PET). Recombinant SHH ligand was conjugated to the bifunctional chelator DOTA. DOTA-SHH was obtained with a total yield of 45%-60% as assessed by HPLC. DOTA-SHH was further characterized using MALDI-MS, ESI-MS with purity > 90%. The conjugate was radiolabeled with 68Ga, with radiochemical purity of >98% and specific activity of 4.3E+05 MBq/gram (theoretical specific activity = 9.18E+09 MBq/gram) as assessed by ITLC and radioHPLC. 68Ga-DOTA-SHH maintains high receptor binding in breast cancer cells and cellular uptake was correlated with PTCH receptor expression levels. Addition of 100-fold excess cold SHH reduced cellular uptake by approximately 90%. PTCH receptor expression is increased in MCF-7 stem cell-enriching culture conditions (mammospheres) and cellular uptake of 68Ga-DOTA-SHH was approximately 12-fold higher in mammosphere MCF-7 cultures compared to the total cell population. These findings demonstrate that chemical modification and radiolabeling of SHH ligand is feasible. Our studies suggest that 68Ga-DOTA-SHH has potential for molecular imaging of breast cancer by PET. Additionally, our studies suggest that 68Ga-DOTA-SHH can potentially identify aggressive tumors that may be rich in cancer stem cells. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4335.

Molecular imaging of breast cancer

Molecular imaging of breast cancer can potentially be used for breast cancer screening, staging, restaging, response evaluation and guiding therapies. Techniques for molecular breast cancer imaging include magnetic resonance imaging (MRI), optical imaging, and radionuclide imaging with positron emission tomography (PET) or single photon emission computed tomography (SPECT). This review focuses on PET and SPECT imaging which can provide sensitive serial non invasive information of tumor characteristics. Most clinical data are gathered on the visualization of general processes such as glucose metabolism with the PET-tracer [(18)F]fluorodeoxyglucose (FDG) and DNA synthesis with [18F]fluoro-L-thymidine (FLT). Increasingly more breast cancer specific targets are imaged such as the estrogen receptor (ER), growth factors and growth factor receptors. Imaging of the ER with the PET tracer 16-alpha-[(18)F]fluoro-17-beta-estradiol (FES) has shown a good correlation between FES tumor uptake and ER density. (111)In-trastuzumab SPECT to image the human epidermal growth factor receptor 2 (HER2) showed that in most patients with metastatic HER2 overexpressing disease more lesions were detected than with conventional staging procedures. The PET tracer (89)Zr-trastuzumab showed excellent, quantifiable, and specific tumor uptake. (111)In-bevacizumab for SPECT and (89)Zr-bevacizumab for PET-imaging have been developed for vascular endothelial growth factor (VEGF) imaging as an angiogenic marker. Lastly, tracers for the receptors EGFR, IGF-1R, PDGF-betaR and the ligand TGFbeta are under development. Although molecular imaging of breast cancer is still not commonly used in daily clinical practice, its application portfolio is expanding rapidly.

2123 Expression of solute carrier genes related to molecular imaging in breast cancer

Background: To determine the role of office-based ultrasound in the early clinical evaluation of breast masses, a consecutive series of diagnostic and interventional breast ultrasounds performed in the surgeon's office were prospectively studied. Methods: A series of 1028 diagnostic ultrasounds were performed in 662 patients over 2 years. The clinical-pathologic data from those patients undergoing ultrasound-guided fine-needle aspiration biopsy (FNAB; n = 267 patients) and/or core needle biopsy (CNB; n = 210 patients) were reviewed. Results: Of the 267 patients undergoing initial FNAB, 179 cysts were identified; 25 patients underwent no additional intervention, and 63 patients with apparently solid lesions underwent subsequent CNB. Core needle biopsy was the initial interventional approach in 147 cases. Of the 210 total patients in whom a CNB was performed, needle biopsy pathologic findings included: fibroadenoma, 57 patients; fibrocystic breast change, 82 patients; carcinoma, 53 patients; abscess/cyst, 12 patients; and other, 6 patients. Operative excision was performed in 106 of these 210 patients. There was a significantly higher false-negative rate among those patients who underwent an initial FNAB (20%; 2/10 patients) as compared with those patients undergoing CNB (3.6%; 2/55 patients; P < .05). No cancers have been identified in those patients undergoing a benign CNB and followed for 6 to 30 months (median, 18 months). Conclusion: Office-based diagnostic ultrasound and interventional ultrasound that uses core needle biopsy is an effective adjunct to the early clinical evaluation of breast masses. (Surgery 1999:126:629-35.)

In vivo carbon nanotube-enhanced non-invasive photoacoustic mapping of the sentinel lymph node

Sentinel lymph node biopsy (SLNB), a less invasive alternative to axillary lymph node dissection (ALND), has become the standard of care for patients with clinically node-negative breast cancer. In SLNB, lymphatic mapping with radio-labeled sulfur colloid and/or blue dye helps identify the sentinel lymph node (SLN), which is most likely to contain metastatic breast cancer. Even though SLNB, using both methylene blue and radioactive tracers, has a high identification rate, it still relies on an invasive surgical procedure, with associated morbidity. In this study, we have demonstrated a non-invasive single-walled carbon nanotube (SWNT)-enhanced photoacoustic (PA) identification of SLN in a rat model. We have successfully imaged the SLN in vivo by PA imaging (793 nm laser source, 5 MHz ultrasonic detector) with high contrast-to-noise ratio (=89) and good resolution (∼500 µm). The SWNTs also show a wideband optical absorption, generating PA signals over an excitation wavelength range of 740–820 nm. Thus, by varying the incident light wavelength to the near infrared region, where biological tissues (hemoglobin, tissue pigments, lipids and water) show low light absorption, the imaging depth is maximized. In the future, functionalization of the SWNTs with targeting groups should allow the molecular imaging of breast cancer.

S21 Molecular imaging of breast cancer

S21 Molecular imaging of breast cancer

Synthesis and chemoselective intramolecular crosslinking of a HER2‐binding affibody

The human epidermal growth factor receptor HER2 has emerged as an important target for molecular imaging of breast cancer. This article presents the design and synthesis of a HER2-targeting affibody molecule with improved stability and tumor targeting capacity, and with potential use as an imaging agent. The 58 aa three-helix bundle protein was assembled using solid-phase peptide synthesis, and a chemoselective ligation strategy was used to establish an intramolecular thioether bond between the side chain thiol group of a cysteine residue, positioned in the loop between helices I and II, and a chloroacetyl group on the side chain amino group of the C-terminal lysine residue. The tethered protein offered an increased thermal stability, with a melting temperature of 64 degrees C, compared to 54 degrees C for the linear control. The ligation did not have a major influence on the HER2 binding affinity, which was 320 and 380 pM for the crosslinked and linear molecules, respectively. Biodistribution studies were performed both in normal and tumor-bearing mice to evaluate the impact of the crosslinking on the in vivo behavior and on the tumor targeting performance. The distribution pattern was characterized by a low uptake in all organs except kidney, and rapid clearance from blood and normal tissue. Crosslinking of the protein resulted in a significantly increased tumor accumulation, rendering the tethered HER2-binding affibody molecule a valuable lead in the development of superior HER2 imaging agents.

Radioiodination of new EGFR inhibitors as potential SPECT agents for molecular imaging of breast cancer

In our search for the development of novel SPECT radioligands for EGFR positive tumours, new potentially irreversible tyrosine kinase (TK) inhibitors are being explored. The radioiodination of N-{4-[(3-chloro-4-fluorophenyl) amino]quinazoline-6-yl}-3-bromopropionamide, a novel EGFR-TK inhibitor synthesised in our laboratory, was accomplished via halogen exchange. Purification by RP-HPLC gave [ 125I]- N-{4-[(3-chloro-4-fluorophenyl)amino]quinazoline-6-yl}-3-iodopropionamide with a radiochemical purity higher than 95% and a high specific activity. In vitro studies indicate that both iodinated quinazoline and its bromo precursor inhibit A431 cell growth and also possess higher potency than the parent quinazoline to inhibit the EGFR autophosphorylation. In vivo stability studies suggest metabolization of the radioiodinated quinazoline indicating a short biological half-life. The in vitro results point out that these quinazoline derivatives could be promising candidates for SPECT imaging of EGFR positive tumours provided that they are selectively modified in order to achieve better in vivo radiochemical stability.

FDG-PET and Beyond: Molecular Breast Cancer Imaging

Positron emission tomography (PET) scanning has gained widespread acceptance for the diagnosis, staging, and management of a variety of malignancies, including breast cancer. This has heralded an exciting new era of molecular imaging research of which using FDG as the primary PET tracer is only the beginning. The fundamental strength of PET over conventional imaging is the ability to convey functional information that even the most exquisitely detailed anatomic image cannot provide. As the standard PET radiotracer in current clinical use, FDG is a glucose analog that is taken up by cells in proportion to their rate of glucose metabolism. The increased glycolytic rate and glucose avidity of malignant cells in comparison to normal tissue is the basis of the ability of FDG-PET imaging to accurately differentiate cancer from benign tissue irregardless of morphology. The level or intensity of FDG uptake on PET is semiquantified and reported as the standardized uptake value (SUV). A multitude of new PET tracers are under development, many of which are aimed at targeting cellular processes that are more specific than glucose metabolism. In relation to breast cancer, these tracers include thymidine analogs such as [F-18]fluoro-L-thymidine (FLT) that target DNA replication as a measure of cell proliferation, annexin V derivatives that evaluate apoptosis, estrogen receptor (ER) tracers such as 16 -[F-18]fluoroestradiol-17 (FES), and engineered antibody fragments that directly target HER-2/neu receptors. In addition to new tracers, scanner technology is also rapidly evolving. Chief among these is the advent of the dual modality PET/CT scanner, which at the very least increases patient convenience by permitting PET and computed tomography (CT) imaging in a single appointment. But perhaps more importantly, initial studies indicate that the sum of the two modalities is better than either used separately and also may be an extremely useful tool in preradiation therapy planning. Other new scanning devices are also being developed, including small gantry PET scanners designed specifically for breast imaging, and handheld PET probes for direct intraoperative localization of tracer-avid tumor foci.