Keynote Conference - Interevent

Symp#24 Cancer
Chair Renata Pasqualini
Integration of in Vivo Phage Display & Targeted nanotechnology and Molecular-genetic Imaging
Renata Pasqualini, Ph.D.
The University of Texas, M D Anderson Cancer Center, USA
Our group has previously reported the design, generation, and construction of AAV/phage (termed AAVP) particles (Hajitou et al.
2006, Hajitou et al. 2007, Soghomonyan et al. 2007) for targeted molecular-genetic imaging. These hybrid vectors containing
prokaryotic and eukaryotic cis-genomic elements have the potential to integrate ligand-directed targeting and molecular-genetic
imaging. In a related line of research, we have used labeled, targeted peptide motifs themselves as imaging tools (Yao et al. 2005,
Marchiò et al. 2004, Arap et al. 2004, Zurita et al. 2004, Cardó-Vila et al. 2003, Chen et al. 2003, Mintz et al. 2003). In pilot
experiments, AAVP-based molecular-genetic imaging appears to be superior in side-by-side comparison to standard imaging because
it provides prediction of therapeutic response in addition to only monitoring (Hajitou et al., PNAS, 2008). Thus, we plan to focus
primarily on the development of AAVP-based molecular-genetic imaging approaches. Finally, we have also designed and developed
nanotechnology-based (i.e., bottom-up self-assembled) biocompatible networks of phage-gold as nano-molecular sensors and
reporters (Souza et al. 2006a, Souza et al. 2006b). This new methodology will be incorporated and will likely prove to be quite
synergistic with AAVP (Souza et al. 2011). Here we used prototypes of this new class of targeted hybrid vectors for therapy and for
molecular-genetic imaging, in conjunction to the discovery of new ligand motifs that target human tumor endothelium. AAVP-based
anti-vascular cancer therapy by targeted TNF in pet dogs with native tumors has also been successful (Paoloni et al. 2009). Ultimately
to generate an “imaging transcriptome” for human tumors. The incorporation of transcriptional targeting (through tissue-specific or
radiation-induced promoters) to ligand-directed AAVP-targeting may enable one to determine a gene (or set of genes) status without
tissue biopsy.
Tumor Cell to Tumor Cell Interaction Drives Cancer Heterogeneity
Webster K. Cavenee
Ludwig Institute for Cancer Research, University of California San Diego, 9500 Gilman Drive, La Jolla, CA 92093-0660 USA
Most efforts to understand the consequences of large-scale genomic mining of data from human tumors have focused on their cellintrinsic
activities both in vitro and in vivo. Because of this, targeted therapeutic approaches have primarily been directed at features
of individual tumor cells and their intrinsic mutations. For example, we have for more than a decade functionally dissected the
amplification and mutation of the epidermal growth factor receptor gene (EGFR), that results in the common and oncogenic EGFRvIII
(ΔEGFR) variant, a signature pathogenetic event in glioblastoma, the most common intracranial tumor. These analyses have allowed
us to develop both small molecule- and antibody-based therapeutics that are now in clinical trials.
Paradoxically, despite its greater intrinsic biological activity than wildtype EGFR (wtEGFR), only a minority of cancer cells in primary
tumors possesses the hallmark ΔEGFR lesion, while the remainder expresses wtEGFR. We hypothesized that the ΔEGFR-expressing
subpopulation has an extrinsic activity that provides enhanced tumorigenicity to the entire tumor cell population, perhaps through a
paracrine mechanism. Using a combination of mixed tumor engraftments and biochemical analysis of paracrine factors and signaling
pathways activation, we determined that human glioma tissues, glioma cell lines, glioma stem cells and primary mouse astrocytes,
that express ΔEGFR each secrete IL-6 and/or LIF cytokines. This then prompts a novel interaction between the receptor that is
common to these cytokines, gp130, and wtEGFR in neighboring cells that express amplified levels of EGFR, resulting in co-receptor
activation and tumor growth enhancement. Ablating IL-6, LIF or gp130 uncouples this cellular cross-talk and potently attenuates
tumor growth enhancement.
These findings demonstrate that the heterogeneity that characterizes GBM, and perhaps other tumors with this feature, does not
occur stochastically. Instead, it results from both intrinsic and extrinsic activities of driver mutations and can be an actively
maintained feature. This illuminates for the first time a heterotypic cancer cell interaction of potential therapeutic significance.
Targeting Adipose Tissue to Prevent Cancer Progression
Wadih Arap, M.D., Ph.D.
The University of Texas, M D Anderson Cancer Center, USA
Human obesity is a leading cause of morbidity and mortality and a financial burden worldwide. Despite efforts in past decades, very
few drugs have been developed for the treatment of obese patients. The paradigm of obesity treatment currently relies on CNS
and/or peripheral metabolic mechanisms to suppress appetite and elevate energy expenditure, or inhibition of fat absorption. Only
two Food FDA-approved drugs for weight loss are currently available in the United States (phentermine and orlistat); most
unfortunately, placebo-subtracted weight losses are small and concerns over side effects limit their use, hence the great therapeutic
challenge. Here we evaluated and validated a new conceptual approach against obesity: targeted induction of apoptosis in blood
vessels supplying white adipose tissue (WAT). Our group is a pioneer in this area and has previously designed and has recently
established adipotide as a prototype in a new class of drugs that target the vascular endothelium of white fat in pre-clinical models of
obese rodents and obese non-human primates. We have chosen to pursue a pilot application of adipotide as a strategy to overcome
the obesity-related tumor-promoting effects of obesity in the context of human prostate cancer progression and recurrence.
Notably, we have received “safe-to-proceed status” from the FDA for the IND application of adipotide; as such, the start of the firstin-human
clinical trial in obese prostate cancer patients is imminent. Our Specific Aims are: (i) To define the metabolic and oncologic
consequences of targeted treatment with adipotide in obese men with prostate cancer. (ii) To lead optimize adipotide derivatives
and dose-limiting toxicity in rodents and non-human primates. In the short-term, imaging guided studies will enable the rapid
translation and drug lead optimization of adipotide and will provide the clinical foundation for approval of an entirely new approach
against human obesity. In the long-term, a successful innovative therapy such as adipotide against human obesity would truly be
transformative with immense public health impact against not only obesity but also against associated patient co-morbidities
including diabetes, metabolic syndrome, arterial hypertension, atherosclerosis, and cancer.
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