Abstract SY03-03: Molecular imaging of intra- and intertumoral heterogeneity of target expression activity: Therapeutic implications
Authors: Gelovani Juri G. 
Published: July 2012

Recent advances in understanding of the genetic and epigenetic abnormalities that induce the development of different tumors provide the opportunity for personalized molecular medicine in cancer patients. However, the effective implementation of tumor targeted therapeutics and fulfilling the promise of personalized molecular medicine will require the development of approaches to identify patients likely to respond to a particular targeted drug or combination of therapeutics as well as approaches to identify patients responding and not responding at an early stage of such treatments. Thus there is an urgent unmet need to develop approaches to efficiently evaluate novel targeted therapeutics and integrate them into clinical practice.

Advanced molecular-genetic and cellular multimodality imaging represents an organic fusion of radiology, nuclear medicine, molecular and cellular biology, which can provide unprecedented ability for noninvasive imaging of various biomarkers for:

• Detection of precancerous lesions

• Early detection of early tumor lesions (i.e., host tissue reaction to intraepithelial neoplasia)

• Tumor profiling and selection of individualized therapies (i.e., via visualization of drug target expression and activity, identification of mutant forms of target proteins)

• Determination of biologically relevant doses (visualization and quantitation of drug target occupancy/activity)

• Early assessment of therapeutic efficacy (visualization of downstream processes, such as glucose metabolism, proliferation, apoptosis, etc.)

• Monitoring the development of resistance to therapy (i.e., imaging PGP expression-activity, acquired resistance mutations in drug targets)

• Monitoring of recurrence (i.e., differentiation of radiation necrosis from recurrence)

• Long-term prognosis

Several novel and previously developed molecular imaging agents and methods (i.e., FDG, FLT, methionine, AnnexinV, perfusion/permeability imaging, etc.) can facilitate the development and clinical translation of novel tumor-targeted molecular therapies. For particular targeted therapies, molecular imaging agents should be developed for visualization and quantitation of the level of target expression and activity or “expression-activity product” (i.e., level of HER2/neu or EGFR expression and activity). In contrast to invasive single or multiple-site biopsies, noninvasive whole body molecular imaging will allow for the assessment of spatial and temporal heterogeneity of target protein expression-activity in primary tumors and different metastatic lesions, monitoring the activity of relevant downstream signaling events, and for imaging more general processes in tumors (metabolism, proliferation, apoptosis, etc.) during therapy. In phase O/I clinical trials of novel molecular-targeted drugs, molecular imaging can provide the means for noninvasive assessment of pharmacokinetics (PK) of a new drug using radiolabeled versions of this drug, as well as pharmacodynamic (PD) assessment of pharmacological micro-dosing by non-invasive repetitive imaging of changes in the activity of downstream effectors and/or processes in tumor tissue and in the whole body.

Furthermore, noninvasive molecular imaging of spatial heterogeneity of target expression and activity should facilitate image-guided therapeutic interventions (i.e., targeted therapies, radiation therapy), as well as image-guided biopsies in areas with high and low target expression activity. The latter should significantly improve the statistical significance and reproducibility of genomic and proteomic analyses and will allow for identification of more reliable biomarkers. Integration molecular imaging of biomarkers and image-guided biopsies into clinical trials and clinical management will allow for the selection of patients likely to respond to particular targeted therapies (to enrich patient population that is likely to respond), for monitoring the biological efficacy of a given targeted therapeutic allowing dose alteration and optimization at an early stage of therapy and allowing for triage to the most appropriate therapy containing patient costs.

Examples of molecular imaging targets include:

• c-Kit mutations in GIST

• EGFR, ALK, K-Ras mutations in NSCLC

• ER, PR, HER2, PI3KCA in breast carcinoma

• AR, neuroendocrine markers in prostate

• C-Kit, B-Raf mutations in melanoma

• K-Ras mutations in colorectal carcinoma

• VERFR2 for angiogenesis in different tumors

Using multitracer and multimodality imaging approaches, it should be possible to develop differential diagnostic algorithms, which will be routinely used by analogy with invasive histopathological and molecular-biological biomarker methods for profiling of individual cancers and for selection (and monitoring) of individualized combination therapies. The latter represents a major shift in product development strategy for industry – from aiming to develop the next “killer application” imaging agent, towards the development of a disease-oriented portfolio of imaging agents, which may be shared between different tumor types and may even be used for diagnosis, profiling, and therapy monitoring of other non-oncologic diseases.

In summary, tumor tissue-derived diagnostic and therapeutic biomarkers as well as corresponding targeted agents for noninvasive imaging should be developed in parallel with novel targeted therapeutics. These imaging agents and approaches should allow for identification of patients that are likely to respond to targeted therapeutics and for triage to the most appropriate therapy. The latter has the potential to greatly improve patient outcome and decrease toxicity. Integration of molecular markers and molecular imaging into clinical trials and clinical management will allow for the selection of patients likely to respond to particular therapies, estimation of responsive vs. nonresponsive tumor burdens (whole body), determination/optimization of biologically effective (not maximum tolerated) doses, assessment of responses to the selected therapies at an early stage of treatment to allow for triage to the most appropriate therapy, and improving the overall outcome.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY03-03. doi:10.1158/1538-7445.AM2011-SY03-03