Download the ESMO 2012 Abstract Book - Oxford Journals
Download the ESMO 2012 Abstract Book - Oxford Journals
Download the ESMO 2012 Abstract Book - Oxford Journals
You also want an ePaper? Increase the reach of your titles
YUMPU automatically turns print PDFs into web optimized ePapers that Google loves.
<strong>ESMO</strong>-EACR Joint Symposium:<br />
Targeted <strong>the</strong>rapies: Promises,<br />
successes and failures<br />
107IN HARNESSING CELLULAR SENESCENCE FOR CANCER<br />
PREVENTION AND THERAPY<br />
P.P. Pandolfi<br />
Medicine, BIDMC/Harvard Medical School, Boston, MA, UNITED STATES OF<br />
AMERICA<br />
We will present exciting new progress at developing what we regard as a new<br />
concept, which we refer to as “pro-senescence <strong>the</strong>rapy”, that aims at utilizing cellular<br />
senescence, a built-in failsafe mechanism in mammalian cell evoked by oncogenic<br />
stress, for cancer prevention and treatment.<br />
We will discuss how this analysis allowed us to identify novel and <strong>the</strong>rapeutically<br />
relevant molecular and biological types of cellular senescence that can be evoked and<br />
potentiated pharmacologically, in turn allowing <strong>the</strong> targeting of cancer stem cells as<br />
well as <strong>the</strong> “quiescent” cancer stem cell pool for <strong>the</strong>rapy.<br />
We will analyze how <strong>the</strong>se new concepts emerged from our analysis and systematic<br />
deconstruction of <strong>the</strong> molecular genetics of human cancer as studied in vivo in<br />
faithful mouse models, with particular emphasis on <strong>the</strong> role of aberrant PTEN/PI3K/<br />
AKT/mTOR signaling in tumorigenesis.<br />
Disclosure: The author has declared no conflicts of interest.<br />
108IN PI3K AND/OR MTOR INHIBITORS: CURRENT STATUS,<br />
FUTURE DIRECTIONS<br />
S. Loi<br />
Breast International Group (BIG), Institute Jules Bordet, Brussels, BELGIUM<br />
The high incidence of molecular aberrations that target <strong>the</strong> phosphatidylinositol-3<br />
kinase (PI3K) pathway in cancer, as well as <strong>the</strong> demonstration that many resistance<br />
mechanisms to drugs also involve this pathway, has unsurprisingly led to high<br />
interest in <strong>the</strong> development of agents to inhibit PI3K signaling. Currently, many<br />
PI3K targeted agents are in phase I/II testing, alone and in combination with<br />
agents that are usual standard of care as well as those that target potential<br />
resistance pathways such as MEK/ERK. Some agents are about to commence phase<br />
III evaluation. Thus far in phase I, <strong>the</strong>re have been signs of activity in <strong>the</strong> advanced<br />
setting for multiple tumor types but surprisingly yet no strong association with<br />
PI3K pathway aberrations such as PIK3CA mutations have been seen. Toxicities<br />
have been reasonably predictable and on-target, including hyperglycaemia,<br />
diarrhea, skin rash, nausea, fatigue and transaminitis Issues that are currently<br />
critical for optimal development in this field are: 1. understanding of who will<br />
benefit- thus far <strong>the</strong> relationship between PIK3CA, AKT1 mutations, PTEN loss<br />
and response to PI3K inhibitors has been not as clear as o<strong>the</strong>r targets such as<br />
BRAF mutants, EML4-ALK rearrangements and HER2 amplification. Activity has<br />
also been observed in genetically unselected cancer populations, though toxicity<br />
may preclude its acceptance in unselected populations if large and meaningful<br />
benefit cannot be shown; 2. Understanding <strong>the</strong> role of dual versus single versus<br />
isotype specific compounds- this may also depend on <strong>the</strong> genetic aberration and<br />
clinical setting; 3. prospective upfront stratification and power to look at mutated<br />
(as well as wild-type) subsets, particularly in early phase clinical trials;<br />
4. Determining rationale combinations with PI3K targeted <strong>the</strong>rapy, which will<br />
undoubtedly depend on <strong>the</strong> setting and cancer type. Addressing <strong>the</strong>se issues, along<br />
with adequate genotyping of <strong>the</strong> tumor, will ensure that we get a clear picture of<br />
<strong>the</strong> molecular background of which patients, tumor types and clinical setting<br />
benefits.<br />
Disclosure: The author has declared no conflicts of interest.<br />
109IN CANCER: AN ANGIOGENIC DISEASE?<br />
Annals of Oncology 23 (Supplement 9): ix59, <strong>2012</strong><br />
doi:10.1093/annonc/mds483<br />
M. Neeman<br />
Faculty of Biology, Weizmann Institute of Science, Rehovot, ISRAEL<br />
The angiogenic switch proposed by Folkman provided a compelling <strong>the</strong>ory for <strong>the</strong> well<br />
recognized phenomenon of tumor dormancy, where tumors show prolonged growth<br />
arrest and remain as microscopic nodules, sometimes for decades before converting into<br />
rapidly progressing cancer. At <strong>the</strong> basis of this <strong>the</strong>ory is <strong>the</strong> idea that diffusion of<br />
nutrients limits growth to a few cell layers, and perfusion, via sprouting of new blood<br />
vessels is required for sustained progression. Hypoxia was recognized as a potent<br />
microenvironmental stimulator of angiogenesis. Hypoxia stabilizes HIF1 alpha resulting<br />
in induced expression of VEGF, a potent vascular permeability factor and <strong>the</strong> central<br />
inducer of angiogenesis. Hypoxia, which affects genetic instability and selection for cells<br />
resistant to apoptosis, is thus also tightly linked with angiogenesis. Angiogenesis,<br />
induced by VEGF is accompanied by rapid elevation of vascular permeability. This<br />
acute effect of VEGF affects tumors in many ways. Extravasated plasma proteins result in<br />
extensive ECM remodeling to form a reactive stroma which supports Inflammation and<br />
tumor cell invasion. Elevated permeability enhances interstitial fluid pressure, limiting<br />
drug delivery. On <strong>the</strong> o<strong>the</strong>r hand, elevated vascular permeability provides thus far one of<br />
<strong>the</strong> most sensitive means for rapid detection and non invasive monitoring of cancer, as<br />
it results in accumulation and retention of contrast media and tumor enhancement on<br />
MRI and CT scans. Angiogenesis provides tumor cells with routes for metastatic spread<br />
to <strong>the</strong> blood circulation, and provide also <strong>the</strong> pressure gradient which drives interstitial<br />
fluid pressure and lymphatic drain and <strong>the</strong>reby facilitates colonization of sentinel lymph<br />
nodes. Despite <strong>the</strong> very strong support for <strong>the</strong> tight association of tumor progression<br />
with induction of angiogenesis, <strong>the</strong> experience with targeting angiogenesis in cancer<br />
<strong>the</strong>rapy has been relatively disappointing, and antiangiogenic <strong>the</strong>rapy is so far nor <strong>the</strong><br />
magic bullet as hoped. Thus clearly it is important to study <strong>the</strong> mechanisms by which<br />
tumors escape from antiangiogenic <strong>the</strong>rapy.<br />
Disclosure: The author has declared no conflicts of interest.<br />
110IN ANTIANGIOGENIC THERAPIES IN THE CLINIC: A<br />
DOUBLE-EDGED SWORD?<br />
D. Miles<br />
Medical Oncology, Mount Vernon Cancer Center, Northwood, UNITED<br />
KINGDOM<br />
Despite <strong>the</strong> initial promise originally proposed by Judah Folkman and o<strong>the</strong>rs,<br />
strategies aimed at tumour vasculature have met with variable success in <strong>the</strong> clinic.<br />
Antibodies and tyrosine kinase inhibitors targeting Vascular Endo<strong>the</strong>lial Growth<br />
Factor (VEGF) are among <strong>the</strong> most highly developed agents targeting angiogenesis.<br />
In indications such as renal cell cancer, where alterations in VEGF are regarded as<br />
<strong>the</strong> principle oncogenic driver, VEGF inhibition has lead to clinically meaningful<br />
improvements in progression-free and overall survival. In more common epi<strong>the</strong>lial<br />
malignancies, <strong>the</strong> efficacy VEGF inhibition has been more modest, possibly as a<br />
consequence of redundancy in <strong>the</strong> angiogenic process. The inherent complexity of<br />
<strong>the</strong> angiogenic response has also made it difficult to identify markers of efficacy, with<br />
a myriad of DNA, serological and dynamic (imaging) metrics being implicated in<br />
prognosis as well as prediction of treatment efficacy and toxicity, e.g., a<br />
second-generation assay of plasma VEGF appears to be of predictive benefit in a<br />
retrospective analysis of two studies in metastatic breast cancer and its use is being<br />
tested prospectively. The controversy surrounding <strong>the</strong> use of anti-angiogenic<br />
approaches in terms of efficacy and regulatory considerations, underscores <strong>the</strong><br />
challenges in <strong>the</strong>ir development: e.g., simple clinical observations that in<br />
malignancies with a relatively long natural history, attributable alterations in<br />
progression-free survival are unlikely to be a surrogate for overall survival. Similarly,<br />
while <strong>the</strong> available data for <strong>the</strong> use of anti-angiogenic agents in <strong>the</strong> adjuvant<br />
treatment of cancer is clearly disappointing it is not perhaps surprising, given <strong>the</strong><br />
likely lack of VEGF dependency of what we understand to be micro-metastatic<br />
disease. A clearer understanding of angiogenesis and its modulation will enable<br />
fur<strong>the</strong>r rational development of this important modality.<br />
Disclosure: The author has declared no conflicts of interest.<br />
Volume 23 | Supplement 9 | September <strong>2012</strong> doi:10.1093/annonc/mds483 | ix59