Page 95 - 2014 Printable Abstract Book
P. 95
A major rationale for investigating DNA repair pathways has been the desire to devise therapeutic
strategies to diminish DNA repair in cancer cells, thereby rendering tumors more susceptible to genotoxic
clinical modalities, including radiotherapy. Alternatively, DNA repair inhibitors can be used as single
agents based on a synthetic lethal (SL) partnership. Synthetic lethality arises when the simultaneous
inactivation of two particular genes or their encoded proteins is lethal, but the individual inactivation of
the genes/proteins leaves cells viable. Thus treatment with an inhibitor of a protein that possesses a SL
partnership with another protein that has been naturally lost or down-regulated in the tumour cells, such
as a tumour suppressor, would confer selective lethality against the tumor cells. Therapeutic advantage
can also be gained through the related concept of “synthetic sickness”, in which co-disruption of two
genes/proteins severely weakens cells to radiation or drug exposure. We have targeted the phosphatase
activity of the DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) because this enzyme plays
a key role in processing strand breaks generated by ionizing radiation and topoisomerase I poisons. Small
molecule inhibitors of PNKP were identified and shown to increase cell sensitivity to radiation and
camptothecin. We also carried out a siRNA-based screen of a “druggable” library of ~7000 genes to
identify potential SL partners of PNKP. We identified several tumor suppressor genes including PTPN6,
which codes for the protein phosphatase SHP-1, and PTEN (Phosphatase and tensin homolog deleted on
chromosome 10). SHP-1 is frequently deficient or absent in lymphomas, leukemias and prostate cancers.
PTEN is one of the most commonly lost tumor suppressors in a variety of cancers. We validated the SL
partnership of PNKP with SHP-1 and PTEN, and in the case of SHP-1 determined that the probable
mechanism for SL is a combination of enhanced production of reactive oxygen species (due to loss of SHP-
1), leading to a toxic build-up of unrepaired DNA SSB and DSB (due to inactivation of PNKP).
S27 NOVEL APPROACHES FOR ADVANCED RADIOTHERAPY- RADIOBIOLOGICAL CHALLENGES
There have been significant advances in the technical delivery of radiotherapy including advanced
image guided and ion-beam approaches. Our understanding of the underlying radiation biology is
changing and this symposium will review the potential of biological based models for optimal treatment
delivery.
(S2701) New advances in radiotherapy and key radiobiological questions. Soren M. Bentzen,
Department of Human Oncology, Madison, WI
(S2702) From dose to biological effect: Biological parameters in proton therapy treatment planning
Harald Paganetti, Massachusetts General, and Boston, MA
Proton therapy treatments are currently planned and delivered assuming that the dose should be
10% lower compared to what would be prescribed using photons, i.e. the effective proton RBE is 1.1 in
comparison to high-energy photons. The use of this generic, spatially invariant RBE within tumor targets
and normal tissue structures disregards the evidence suggesting that proton RBE varies. It increases with
increasing LET, which suggests the RBE in the distal edge of a spread out Bragg peak (SOBP) is larger than
the RBE in the plateau region or proximal part of a SOBP. There are concerns that we may under- or
overestimate the RBE for certain organs and that this could potentially impact the clinical efficacy of
proton therapy. Variations in RBE could impact tumor control as well as normal tissue complications. On
93 | P a g e
strategies to diminish DNA repair in cancer cells, thereby rendering tumors more susceptible to genotoxic
clinical modalities, including radiotherapy. Alternatively, DNA repair inhibitors can be used as single
agents based on a synthetic lethal (SL) partnership. Synthetic lethality arises when the simultaneous
inactivation of two particular genes or their encoded proteins is lethal, but the individual inactivation of
the genes/proteins leaves cells viable. Thus treatment with an inhibitor of a protein that possesses a SL
partnership with another protein that has been naturally lost or down-regulated in the tumour cells, such
as a tumour suppressor, would confer selective lethality against the tumor cells. Therapeutic advantage
can also be gained through the related concept of “synthetic sickness”, in which co-disruption of two
genes/proteins severely weakens cells to radiation or drug exposure. We have targeted the phosphatase
activity of the DNA repair enzyme polynucleotide kinase/phosphatase (PNKP) because this enzyme plays
a key role in processing strand breaks generated by ionizing radiation and topoisomerase I poisons. Small
molecule inhibitors of PNKP were identified and shown to increase cell sensitivity to radiation and
camptothecin. We also carried out a siRNA-based screen of a “druggable” library of ~7000 genes to
identify potential SL partners of PNKP. We identified several tumor suppressor genes including PTPN6,
which codes for the protein phosphatase SHP-1, and PTEN (Phosphatase and tensin homolog deleted on
chromosome 10). SHP-1 is frequently deficient or absent in lymphomas, leukemias and prostate cancers.
PTEN is one of the most commonly lost tumor suppressors in a variety of cancers. We validated the SL
partnership of PNKP with SHP-1 and PTEN, and in the case of SHP-1 determined that the probable
mechanism for SL is a combination of enhanced production of reactive oxygen species (due to loss of SHP-
1), leading to a toxic build-up of unrepaired DNA SSB and DSB (due to inactivation of PNKP).
S27 NOVEL APPROACHES FOR ADVANCED RADIOTHERAPY- RADIOBIOLOGICAL CHALLENGES
There have been significant advances in the technical delivery of radiotherapy including advanced
image guided and ion-beam approaches. Our understanding of the underlying radiation biology is
changing and this symposium will review the potential of biological based models for optimal treatment
delivery.
(S2701) New advances in radiotherapy and key radiobiological questions. Soren M. Bentzen,
Department of Human Oncology, Madison, WI
(S2702) From dose to biological effect: Biological parameters in proton therapy treatment planning
Harald Paganetti, Massachusetts General, and Boston, MA
Proton therapy treatments are currently planned and delivered assuming that the dose should be
10% lower compared to what would be prescribed using photons, i.e. the effective proton RBE is 1.1 in
comparison to high-energy photons. The use of this generic, spatially invariant RBE within tumor targets
and normal tissue structures disregards the evidence suggesting that proton RBE varies. It increases with
increasing LET, which suggests the RBE in the distal edge of a spread out Bragg peak (SOBP) is larger than
the RBE in the plateau region or proximal part of a SOBP. There are concerns that we may under- or
overestimate the RBE for certain organs and that this could potentially impact the clinical efficacy of
proton therapy. Variations in RBE could impact tumor control as well as normal tissue complications. On
93 | P a g e
