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Harnessing Cellular Senescence for Cancer Prevention and Therapy
Annals of Oncology 23 (Supplement 9): ix59, 2012 doi:10.1093/annonc/mds483
ESMO-EACR Joint Symposium: Targeted therapies: Promises, successes and failures 107IN
HARNESSING CELLULAR SENESCENCE FOR CANCER PREVENTION AND THERAPY
P.P. Pandolfi Medicine, BIDMC/Harvard Medical School, Boston, MA, UNITED STATES OF AMERICA
108IN
PI3K AND/OR MTOR INHIBITORS: CURRENT STATUS, FUTURE DIRECTIONS
S. Loi Breast International Group (BIG), Institute Jules Bordet, Brussels, BELGIUM The high incidence of molecular aberrations that target the phosphatidylinositol-3 kinase (PI3K) pathway in cancer, as well as the demonstration that many resistance mechanisms to drugs also involve this pathway, has unsurprisingly led to high interest in the development of agents to inhibit PI3K signaling. Currently, many PI3K targeted agents are in phase I/II testing, alone and in combination with agents that are usual standard of care as well as those that target potential resistance pathways such as MEK/ERK. Some agents are about to commence phase III evaluation. Thus far in phase I, there have been signs of activity in the advanced setting for multiple tumor types but surprisingly yet no strong association with PI3K pathway aberrations such as PIK3CA mutations have been seen. Toxicities have been reasonably predictable and on-target, including hyperglycaemia, diarrhea, skin rash, nausea, fatigue and transaminitis Issues that are currently critical for optimal development in this field are: 1. understanding of who will benefit- thus far the relationship between PIK3CA, AKT1 mutations, PTEN loss and response to PI3K inhibitors has been not as clear as other targets such as BRAF mutants, EML4-ALK rearrangements and HER2 amplification. Activity has also been observed in genetically unselected cancer populations, though toxicity may preclude its acceptance in unselected populations if large and meaningful benefit cannot be shown; 2. Understanding the role of dual versus single versus isotype specific compounds- this may also depend on the genetic aberration and clinical setting; 3. prospective upfront stratification and power to look at mutated (as well as wild-type) subsets, particularly in early phase clinical trials; 4. Determining rationale combinations with PI3K targeted therapy, which will undoubtedly depend on the setting and cancer type. Addressing these issues, along with adequate genotyping of the tumor, will ensure that we get a clear picture of the molecular background of which patients, tumor types and clinical setting benefits. Disclosure: The author has declared no conflicts of interest.
Volume 23 | Supplement 9 | September 2012
CANCER: AN ANGIOGENIC DISEASE?
M. Neeman Faculty of Biology, Weizmann Institute of Science, Rehovot, ISRAEL The angiogenic switch proposed by Folkman provided a compelling theory for the well recognized phenomenon of tumor dormancy, where tumors show prolonged growth arrest and remain as microscopic nodules, sometimes for decades before converting into rapidly progressing cancer. At the basis of this theory is the idea that diffusion of nutrients limits growth to a few cell layers, and perfusion, via sprouting of new blood vessels is required for sustained progression. Hypoxia was recognized as a potent microenvironmental stimulator of angiogenesis. Hypoxia stabilizes HIF1 alpha resulting in induced expression of VEGF, a potent vascular permeability factor and the central inducer of angiogenesis. Hypoxia, which affects genetic instability and selection for cells resistant to apoptosis, is thus also tightly linked with angiogenesis. Angiogenesis, induced by VEGF is accompanied by rapid elevation of vascular permeability. This acute effect of VEGF affects tumors in many ways. Extravasated plasma proteins result in extensive ECM remodeling to form a reactive stroma which supports Inflammation and tumor cell invasion. Elevated permeability enhances interstitial fluid pressure, limiting drug delivery. On the other hand, elevated vascular permeability provides thus far one of the most sensitive means for rapid detection and non invasive monitoring of cancer, as it results in accumulation and retention of contrast media and tumor enhancement on MRI and CT scans. Angiogenesis provides tumor cells with routes for metastatic spread to the blood circulation, and provide also the pressure gradient which drives interstitial fluid pressure and lymphatic drain and thereby facilitates colonization of sentinel lymph nodes. Despite the very strong support for the tight association of tumor progression with induction of angiogenesis, the experience with targeting angiogenesis in cancer therapy has been relatively disappointing, and antiangiogenic therapy is so far nor the magic bullet as hoped. Thus clearly it is important to study the mechanisms by which tumors escape from antiangiogenic therapy. Disclosure: The author has declared no conflicts of interest.
110IN
ANTIANGIOGENIC THERAPIES IN THE CLINIC: A DOUBLE-EDGED SWORD?
D. Miles Medical Oncology, Mount Vernon Cancer Center, Northwood, UNITED KINGDOM Despite the initial promise originally proposed by Judah Folkman and others, strategies aimed at tumour vasculature have met with variable success in the clinic. Antibodies and tyrosine kinase inhibitors targeting Vascular Endothelial Growth Factor (VEGF) are among the most highly developed agents targeting angiogenesis. In indications such as renal cell cancer, where alterations in VEGF are regarded as the principle oncogenic driver, VEGF inhibition has lead to clinically meaningful improvements in progression-free and overall survival. In more common epithelial malignancies, the efficacy VEGF inhibition has been more modest, possibly as a consequence of redundancy in the angiogenic process. The inherent complexity of the angiogenic response has also made it difficult to identify markers of efficacy, with a myriad of DNA, serological and dynamic (imaging) metrics being implicated in prognosis as well as prediction of treatment efficacy and toxicity, e.g., a second-generation assay of plasma VEGF appears to be of predictive benefit in a retrospective analysis of two studies in metastatic breast cancer and its use is being tested prospectively. The controversy surrounding the use of anti-angiogenic approaches in terms of efficacy and regulatory considerations, underscores the challenges in their development: e.g., simple clinical observations that in malignancies with a relatively long natural history, attributable alterations in progression-free survival are unlikely to be a surrogate for overall survival. Similarly, while the available data for the use of anti-angiogenic agents in the adjuvant treatment of cancer is clearly disappointing it is not perhaps surprising, given the likely lack of VEGF dependency of what we understand to be micro-metastatic disease. A clearer understanding of angiogenesis and its modulation will enable further rational development of this important modality. Disclosure: The author has declared no conflicts of interest.
doi:10.1093/annonc/mds483 | ix
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 6, 2016
We will present exciting new progress at developing what we regard as a new concept, which we refer to as “pro-senescence therapy”, that aims at utilizing cellular senescence, a built-in failsafe mechanism in mammalian cell evoked by oncogenic stress, for cancer prevention and treatment. We will discuss how this analysis allowed us to identify novel and therapeutically relevant molecular and biological types of cellular senescence that can be evoked and potentiated pharmacologically, in turn allowing the targeting of cancer stem cells as well as the “quiescent” cancer stem cell pool for therapy. We will analyze how these new concepts emerged from our analysis and systematic deconstruction of the molecular genetics of human cancer as studied in vivo in faithful mouse models, with particular emphasis on the role of aberrant PTEN/PI3K/ AKT/mTOR signaling in tumorigenesis. Disclosure: The author has declared no conflicts of interest.
109IN
ESMO-EACR Joint Symposium: Targeted therapies: Promises, successes and failures 107IN
HARNESSING CELLULAR SENESCENCE FOR CANCER PREVENTION AND THERAPY
P.P. Pandolfi Medicine, BIDMC/Harvard Medical School, Boston, MA, UNITED STATES OF AMERICA
108IN
PI3K AND/OR MTOR INHIBITORS: CURRENT STATUS, FUTURE DIRECTIONS
S. Loi Breast International Group (BIG), Institute Jules Bordet, Brussels, BELGIUM The high incidence of molecular aberrations that target the phosphatidylinositol-3 kinase (PI3K) pathway in cancer, as well as the demonstration that many resistance mechanisms to drugs also involve this pathway, has unsurprisingly led to high interest in the development of agents to inhibit PI3K signaling. Currently, many PI3K targeted agents are in phase I/II testing, alone and in combination with agents that are usual standard of care as well as those that target potential resistance pathways such as MEK/ERK. Some agents are about to commence phase III evaluation. Thus far in phase I, there have been signs of activity in the advanced setting for multiple tumor types but surprisingly yet no strong association with PI3K pathway aberrations such as PIK3CA mutations have been seen. Toxicities have been reasonably predictable and on-target, including hyperglycaemia, diarrhea, skin rash, nausea, fatigue and transaminitis Issues that are currently critical for optimal development in this field are: 1. understanding of who will benefit- thus far the relationship between PIK3CA, AKT1 mutations, PTEN loss and response to PI3K inhibitors has been not as clear as other targets such as BRAF mutants, EML4-ALK rearrangements and HER2 amplification. Activity has also been observed in genetically unselected cancer populations, though toxicity may preclude its acceptance in unselected populations if large and meaningful benefit cannot be shown; 2. Understanding the role of dual versus single versus isotype specific compounds- this may also depend on the genetic aberration and clinical setting; 3. prospective upfront stratification and power to look at mutated (as well as wild-type) subsets, particularly in early phase clinical trials; 4. Determining rationale combinations with PI3K targeted therapy, which will undoubtedly depend on the setting and cancer type. Addressing these issues, along with adequate genotyping of the tumor, will ensure that we get a clear picture of the molecular background of which patients, tumor types and clinical setting benefits. Disclosure: The author has declared no conflicts of interest.
Volume 23 | Supplement 9 | September 2012
CANCER: AN ANGIOGENIC DISEASE?
M. Neeman Faculty of Biology, Weizmann Institute of Science, Rehovot, ISRAEL The angiogenic switch proposed by Folkman provided a compelling theory for the well recognized phenomenon of tumor dormancy, where tumors show prolonged growth arrest and remain as microscopic nodules, sometimes for decades before converting into rapidly progressing cancer. At the basis of this theory is the idea that diffusion of nutrients limits growth to a few cell layers, and perfusion, via sprouting of new blood vessels is required for sustained progression. Hypoxia was recognized as a potent microenvironmental stimulator of angiogenesis. Hypoxia stabilizes HIF1 alpha resulting in induced expression of VEGF, a potent vascular permeability factor and the central inducer of angiogenesis. Hypoxia, which affects genetic instability and selection for cells resistant to apoptosis, is thus also tightly linked with angiogenesis. Angiogenesis, induced by VEGF is accompanied by rapid elevation of vascular permeability. This acute effect of VEGF affects tumors in many ways. Extravasated plasma proteins result in extensive ECM remodeling to form a reactive stroma which supports Inflammation and tumor cell invasion. Elevated permeability enhances interstitial fluid pressure, limiting drug delivery. On the other hand, elevated vascular permeability provides thus far one of the most sensitive means for rapid detection and non invasive monitoring of cancer, as it results in accumulation and retention of contrast media and tumor enhancement on MRI and CT scans. Angiogenesis provides tumor cells with routes for metastatic spread to the blood circulation, and provide also the pressure gradient which drives interstitial fluid pressure and lymphatic drain and thereby facilitates colonization of sentinel lymph nodes. Despite the very strong support for the tight association of tumor progression with induction of angiogenesis, the experience with targeting angiogenesis in cancer therapy has been relatively disappointing, and antiangiogenic therapy is so far nor the magic bullet as hoped. Thus clearly it is important to study the mechanisms by which tumors escape from antiangiogenic therapy. Disclosure: The author has declared no conflicts of interest.
110IN
ANTIANGIOGENIC THERAPIES IN THE CLINIC: A DOUBLE-EDGED SWORD?
D. Miles Medical Oncology, Mount Vernon Cancer Center, Northwood, UNITED KINGDOM Despite the initial promise originally proposed by Judah Folkman and others, strategies aimed at tumour vasculature have met with variable success in the clinic. Antibodies and tyrosine kinase inhibitors targeting Vascular Endothelial Growth Factor (VEGF) are among the most highly developed agents targeting angiogenesis. In indications such as renal cell cancer, where alterations in VEGF are regarded as the principle oncogenic driver, VEGF inhibition has lead to clinically meaningful improvements in progression-free and overall survival. In more common epithelial malignancies, the efficacy VEGF inhibition has been more modest, possibly as a consequence of redundancy in the angiogenic process. The inherent complexity of the angiogenic response has also made it difficult to identify markers of efficacy, with a myriad of DNA, serological and dynamic (imaging) metrics being implicated in prognosis as well as prediction of treatment efficacy and toxicity, e.g., a second-generation assay of plasma VEGF appears to be of predictive benefit in a retrospective analysis of two studies in metastatic breast cancer and its use is being tested prospectively. The controversy surrounding the use of anti-angiogenic approaches in terms of efficacy and regulatory considerations, underscores the challenges in their development: e.g., simple clinical observations that in malignancies with a relatively long natural history, attributable alterations in progression-free survival are unlikely to be a surrogate for overall survival. Similarly, while the available data for the use of anti-angiogenic agents in the adjuvant treatment of cancer is clearly disappointing it is not perhaps surprising, given the likely lack of VEGF dependency of what we understand to be micro-metastatic disease. A clearer understanding of angiogenesis and its modulation will enable further rational development of this important modality. Disclosure: The author has declared no conflicts of interest.
doi:10.1093/annonc/mds483 | ix
Downloaded from http://annonc.oxfordjournals.org/ by guest on June 6, 2016
We will present exciting new progress at developing what we regard as a new concept, which we refer to as “pro-senescence therapy”, that aims at utilizing cellular senescence, a built-in failsafe mechanism in mammalian cell evoked by oncogenic stress, for cancer prevention and treatment. We will discuss how this analysis allowed us to identify novel and therapeutically relevant molecular and biological types of cellular senescence that can be evoked and potentiated pharmacologically, in turn allowing the targeting of cancer stem cells as well as the “quiescent” cancer stem cell pool for therapy. We will analyze how these new concepts emerged from our analysis and systematic deconstruction of the molecular genetics of human cancer as studied in vivo in faithful mouse models, with particular emphasis on the role of aberrant PTEN/PI3K/ AKT/mTOR signaling in tumorigenesis. Disclosure: The author has declared no conflicts of interest.
109IN