Page 48 - 2014 Printable Abstract Book
P. 48
influence on cancer treatment will aid the development of therapeutic interventions to overcome its
detriments which should ultimately lead to improvements in both local tumor control and overall survival
in cancer patients treated with anticancer therapies.
(S801) Tumor Hypoxia and Genomic Instability: A Way Forward in Precision Cancer Medicine.
Robert G. Bristow, Princess Margaret Hospital, Toronto, Canada
Sub-regions of hypoxia exist within all tumors and the presence of intratumoral hypoxia has an
adverse impact on patient prognosis. Tumor hypoxia can increase metastatic capacity and lead to
resistance to chemotherapy and radiotherapy. Hypoxia also leads to altered transcription and translation
of a number of DNA damage response and repair genes. Hypoxia can also increase the rate of mutation.
Altogether, this leads to functional defects in: homologous recombination (HR), non-homologous end-
joining (NHEJ), mismatch repair (MMR) and base excision repair (BER). Therefore, tumor cell adaptation
to the hypoxic microenvironment can drive genetic instability and malignant progression. However, these
DNA repair defects may also provide potentially novel therapeutic approaches to specifically target repair-
deficient hypoxic tumor cells. These types of collateral sensitivities can be described by a "contextual
synthetic lethality" whereby the cell defects caused by the tumor microenvironment renders hypoxic cells
sensitive to inhibition of back-up DNA repair pathways. For example, we have shown that HR-defective
hypoxic tumor cells can be sensitized to PARP inhibition, mitomycin C and cisplatin; whereas, BER-
defective hypoxic cells can be sensitized to single-strand break inducing agents or MNNG. HR-defective
cells may also have a decreased oxygen enhancement ratio (OER) following ionizing radiation when
compared to HR-proficient hypoxic cells. Biomarkers which reflect DNA repair defects and aggressive
tumor cell phenotypes are required to clinically operationalize these concepts into strategies for precision
cancer medicine of patients with hypoxic tumors.
(S802) Impact of the Microenvironment on Drug Penetration and Therapeutic Resistance.
Andrew I. Minchinton, BC Cancer Research Centre, Vancouver, Canada
The tumor microenvironment is increasingly recognized as playing a critical factor in determining
the effectiveness of cancer therapy. The response of tumors to radiation therapy has long been known to
be significantly influenced by molecular oxygen. As extravascular distance increases oxygen tension
decreases, creating gradients that also affect cellular metabolism and proliferation kinetics such that they
influence response to antiproliferatives and other cancer therapeutics. The large inter-vascular distances
often encountered in the tumor microenvironment exacerbate molecular mechanisms of drug resistance
by creating a barrier to drug access. Drugs may have difficulty achieving adequate supply in the tumour
blood vessels, or the high pressures and low bulk flow may limit flux through tissues, and many drugs are
consumed by the highly proliferative perivascular cells. These effects have been demonstrated to impact
numerous small molecules and are intuitively an even bigger problem for the many nanotherapeutics in
development that include everything from monoclonal antibodies (8 nm diameter) to liposomes (40-60
nm) and even larger particles. While the leaky vasculature of tumour vessels creates an opportunity for
selective delivery and accumulation of large particles in tumour tissues, the same abnormal vessels create
the microenvironment of high pressure with accompanying low bulk flow. Highly proliferative tumour
cells and the varying amounts of infiltrative stromal cells create an environment of high stress and
46 | P a g e
detriments which should ultimately lead to improvements in both local tumor control and overall survival
in cancer patients treated with anticancer therapies.
(S801) Tumor Hypoxia and Genomic Instability: A Way Forward in Precision Cancer Medicine.
Robert G. Bristow, Princess Margaret Hospital, Toronto, Canada
Sub-regions of hypoxia exist within all tumors and the presence of intratumoral hypoxia has an
adverse impact on patient prognosis. Tumor hypoxia can increase metastatic capacity and lead to
resistance to chemotherapy and radiotherapy. Hypoxia also leads to altered transcription and translation
of a number of DNA damage response and repair genes. Hypoxia can also increase the rate of mutation.
Altogether, this leads to functional defects in: homologous recombination (HR), non-homologous end-
joining (NHEJ), mismatch repair (MMR) and base excision repair (BER). Therefore, tumor cell adaptation
to the hypoxic microenvironment can drive genetic instability and malignant progression. However, these
DNA repair defects may also provide potentially novel therapeutic approaches to specifically target repair-
deficient hypoxic tumor cells. These types of collateral sensitivities can be described by a "contextual
synthetic lethality" whereby the cell defects caused by the tumor microenvironment renders hypoxic cells
sensitive to inhibition of back-up DNA repair pathways. For example, we have shown that HR-defective
hypoxic tumor cells can be sensitized to PARP inhibition, mitomycin C and cisplatin; whereas, BER-
defective hypoxic cells can be sensitized to single-strand break inducing agents or MNNG. HR-defective
cells may also have a decreased oxygen enhancement ratio (OER) following ionizing radiation when
compared to HR-proficient hypoxic cells. Biomarkers which reflect DNA repair defects and aggressive
tumor cell phenotypes are required to clinically operationalize these concepts into strategies for precision
cancer medicine of patients with hypoxic tumors.
(S802) Impact of the Microenvironment on Drug Penetration and Therapeutic Resistance.
Andrew I. Minchinton, BC Cancer Research Centre, Vancouver, Canada
The tumor microenvironment is increasingly recognized as playing a critical factor in determining
the effectiveness of cancer therapy. The response of tumors to radiation therapy has long been known to
be significantly influenced by molecular oxygen. As extravascular distance increases oxygen tension
decreases, creating gradients that also affect cellular metabolism and proliferation kinetics such that they
influence response to antiproliferatives and other cancer therapeutics. The large inter-vascular distances
often encountered in the tumor microenvironment exacerbate molecular mechanisms of drug resistance
by creating a barrier to drug access. Drugs may have difficulty achieving adequate supply in the tumour
blood vessels, or the high pressures and low bulk flow may limit flux through tissues, and many drugs are
consumed by the highly proliferative perivascular cells. These effects have been demonstrated to impact
numerous small molecules and are intuitively an even bigger problem for the many nanotherapeutics in
development that include everything from monoclonal antibodies (8 nm diameter) to liposomes (40-60
nm) and even larger particles. While the leaky vasculature of tumour vessels creates an opportunity for
selective delivery and accumulation of large particles in tumour tissues, the same abnormal vessels create
the microenvironment of high pressure with accompanying low bulk flow. Highly proliferative tumour
cells and the varying amounts of infiltrative stromal cells create an environment of high stress and
46 | P a g e
