Center for Cancer Nanotechnology Excellence
and Translation (CCNE-T)
Overall CCNE-T Vision
Like the National Cancer Institute (NCI), we believe that nanoscience applied to cancer research is a critical approach for the elimination of cancer. We are convinced that nanotechnology will make a significant impact on cancer diagnosis and management in potentially revolutionary ways. In vitro diagnostics used in conjunction with in vivo molecular imaging can markedly impact future cancer patient management by providing a synergy that neither strategy alone can offer. Nanotechnology can significantly advance both in vitro diagnostics through proteomic and circulating tumor cell nanosensors and in vivo diagnostics through nanoparticles for molecular imaging. The areas of earlier cancer detection and the prediction and monitoring of response to anti-cancer therapies are both very important applications of nanotechnology with near-term clinical translational potential. The earlier detection of relevant cancers that are aggressive is a major challenge for the cancer community. Earlier intervention will greatly improve patient outcomes. If we could detect tumors as small as ~1 mm3 using multiple proteins present in the blood and verify the presence and location of the tumor with imaging, we could cost-effectively detect and manage cancer. Currently, many patients endure multiple therapeutic interventions once their cancer has been detected until a successful therapeutic regimen can be found. If methods could be developed that would allow the accurate prediction and assessment of a given individual's response to therapy, then marked improvements in cancer management would likely follow. Our overall vision for achieving this is outlined in the figure below.
The figure above is the merger of nano-based in vitro and in vivo diagnostics allows us to predict and monitor response to anti-cancer therapies (A) and the earlier detection of cancer (B). Our existing program (CCNE-TR) focuses on the strategy shown in A while our current program (CCNE-T) encompasses both predicting and monitoring strategies as well as strategies for earlier detection of cancer (A&B).
We now have the potential, with ultra-sensitive nanosensors, to detect relatively small tumor burdens (perhaps as small as ~1 mm3) using multiple protein biomarkers present in the blood. We also have the potential to molecularly image these early stage cancers in vivo using novel nanoparticles that allow signal amplification and multiplexing. Using nanotechnology, we should also be able to predict which patients will likely respond to a specific anti-cancer therapy and, at the same time, monitor their response to those therapies. This includes nanotechnologies that can measure changes in relevant blood proteins pre- and post-treatment as well as nanotechnologies that capture and interrogate circulating tumor cells pre- and post-therapy. In addition, molecular imaging with existing strategies (e.g., PET-CT) and novel nanoparticle-based imaging technologies can help identify the heterogeneity of tumor response at multiple metastatic sites. Through an integrated, cohesive five-year plan that builds on our first four years of significant progress, we are pursuing the use of in vitro protein nanosensors and in vivo nanoparticles for next generation molecular imaging. As shown in Figure N1.1. above, our vision is that eventually patients will have their cancers detected at much earlier stages through blood biomarkers. Results from these blood tests will be verified by molecular imaging that will also localize the tumors prior to treatment. Post-treatment and potentially during treatment, patient response will be evaluated by blood analysis, without another tumor biopsy, and molecular imaging to ensure the accurate differentiation of responders from non-responders. To achieve this clinical potential, nanotechnology will continue to be tested in small animal models and multiple clinical trials funded through other mechanisms.
The Secondary Focus is Cancer Early Detection
Earlier detection of relevant cancer is a more difficult problem than later stage disease because there are substantially fewer tumor cells and molecular targets to detect. We are, however, ready to take on this challenge as a secondary focus because our strategies are now more mature and we are able to leverage support from the Canary Foundation and its focus on early cancer detection. Many cancers are detected in their late stages of progression at which point oncologists do not have many choices for treatment options that can lead to a significant chance of cure. This is an especially significant problem for lung and ovarian cancer since they are “the silent killers”. It is not only important to detect cancer early, but to detect the relevant ‘silent’ cancer early. The search for pertinent blood and tissue biomarkers for the early cancer detection problem is difficult but has been aggressively tackled by the Canary Foundation and the NCI Early Detection Research Network (EDRN). In this proposal, we will attempt to address the early cancer detection problem by the development and utilization of exquisitely sensitive, multiplexing capable, wide-dynamic detection range cancer specific magneto-nano sensors (P2a). We will also develop novel molecular imaging instruments (trans-vaginal photoacoustic probes) (P4) and novel gold-based nanoparticles (P1 and P4) for applications in the early detection of ovarian cancer. It is not clear that capture of circulating tumor cells and cancer stem cells (P2b) and single tumor cell analysis (P3) are relevant to the early detection problem since finding such cells in the blood may be a sign that the cancer is already beyond the early detection stage. Therefore, for early cancer detection, our primary focus will be on blood protein biomarkers and nano-molecular imaging. It is also important to note that our recently funded Ovarian SPORE, two new applications to the EDRN mechanism, and significant funding from the Canary Foundation will help us to succeed in the area of earlier cancer detection.
Evolution of the Program and Structure of CCNE-TR as compared to CCNE-T
The CCNE-TR has evolved significantly over the last 3.5 years. Several of the original groups are not directly funded in this CCNE-T because their projects have matured and they are now part of other grants that weave our network together. Of note, we had a significant component involving biomarker discovery for biomarkers of response to HER-kinase axis treatment in lung cancer (Fred Hutchinson Cancer Research Center Investigators). This component is not part of the CCNE-T because we already have good biomarker leads for response to lung cancer therapy from the hard efforts over the last few years, and new biomarker searches in early detection are already being funded by the Canary Foundation and our Ovarian SPORE. It is also important to note that the group at Cedars-Sinai have now moved their entire programs to the University of Southern California (USC) and that is why Cedars-Sinai is no longer involved in the CCNE-T. In addition, due to significant growth in activity between UCB and Stanford, including Dr. Luke Lee who is currently doing a sabbatical at Stanford for one year. We have 6 groups involved in the current CCNE-T (Stanford, UCB, UCLA, USC, MIT and LBNL). This number is needed because our original CCNE was large and the current momentum on several projects requires the proposed institutions.
Where it Begins
While nanotechnology has the potential to greatly impact ex vivo proteomics and in vivo diagnostics through molecular imaging for early cancer detection, it must first be validated through the more tractable problem of impacting the management of later stage cancers. Because there are more cancer cells present in advanced disease, there are likely to be more changes in the proteome to detect ex vivo as well as more protein targets for molecular imaging probes in vivo. With its capacity to provide enormous sensitivity, throughput, and flexibility, nanotechnology has the potential to profoundly impact cancer patient management in the coming years.