Novel radio-therapeutic deliveries to induce apoptosis in epithelial and endothelial compartment of solid tumors : A Pre-Clinical and Clinical Perspective Mansoor M. Ahmed PhD Staff Scientist http://www.biologyofcancer.org Weis Center for Research, Geisinger Clinic, Danville, PA 17822
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Novel radio-therapeutic deliveries to induce apoptosis in epithelial and endothelial compartment of solid tumors : A Pre- Clinical and Clinical Perspective.
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Novel radio-therapeutic deliveries to induce apoptosis in epithelial and endothelial compartment of solid tumors : A Pre-
Clinical and Clinical Perspective
Mansoor M. Ahmed PhDStaff Scientist
http://www.biologyofcancer.org
Weis Center for Research, Geisinger Clinic, Danville, PA 17822
Low-dose fractionated Low-dose fractionated radiation as a chemo-radiation as a chemo-
potentiatorpotentiator
This is how the idea started!!!!
• When paclitaxel and radiation were combined, an enhanced radiosensitizing effect (P < 0.05) was observed in HCT-116 cells (SF(2) = 0.138; D(0) = 103 cGy), whereas in HT-29 cells no significant radiosensitization of paclitaxel was observed (SF(2) = 0.608; D(0) = 306 cGy).
• However, pretreatment with paclitaxel followed by multifractionated low dose radiation (0.5- or 1-Gy fractions for a total dose of 2 Gy) significantly enhanced the radiosensitizing effect in both HCT-116 and HT-29 cells.
• The results of the current study suggested that multifractionated radiation given at very low doses after exposure of cells to paclitaxel conferred a potent radiation sensitizing effect irrespective of p53 status.
* Median survival for all 10 patients is 10 months
(range 4 - 37).
Pre Treatment Post Treatment
Pre Treatment Post Treatment
ConclusionsConclusions
LD-UART is well tolerated at 60cGy per fraction when combined with gemcitabine
Given the encouraging radiographic responses and median survival of 10 months in this poor prognostic group of patients, a phase II evaluation is warranted and ongoing
LD-UART is well tolerated at 60cGy per fraction when combined with gemcitabine
Given the encouraging radiographic responses and median survival of 10 months in this poor prognostic group of patients, a phase II evaluation is warranted and ongoing
Future ConsiderationsFuture Considerations
There are many questions yet to be answered and a great deal of opportunity for LDFRT
• ?? mechanism, sequence, timing, etc.
In the meantime…
LDFRT = “r”
Sites of Opportunity
Colorectal CA (FOLFOX) rFOLFOX
Hodgkins Lymphoma (ABVD) rABVD
NHL (CHOP) rRCHOP
Breast Cancer (CMF) rAC-T
Ovarian (Taxotere) rTaxotere
H&N (CarboTaxol) rCarboTaxol
Etc..
There are many questions yet to be answered and a great deal of opportunity for LDFRT
• ?? mechanism, sequence, timing, etc.
In the meantime…
LDFRT = “r”
Sites of Opportunity
Colorectal CA (FOLFOX) rFOLFOX
Hodgkins Lymphoma (ABVD) rABVD
NHL (CHOP) rRCHOP
Breast Cancer (CMF) rAC-T
Ovarian (Taxotere) rTaxotere
H&N (CarboTaxol) rCarboTaxol
Etc..
Ionizing radiation
ATM ATM
AutophosphorylationChromatin changes
ReactiveOxygenSpecies
Bax Cell Death
ActivationCaspases
EGR-1
Ras AKT/PI3-K
NFB
Bcl-2
TNF-
MDR1
Chemo-Resistance
SurvivalProliferation
ATMP
ATMP
ATMP
p53 P
Substratephosphorylation
ATMP
Nbs1P
ATM PBrca1P
p21 waf1/cip1 G1 Arrest
DNA Repair
Focus Formation
DNA repair process is not activated by LDFRT
Ionizing radiation
ATM ATM
AutophosphorylationChromatin changes
ReactiveOxygenSpecies
Bax
Ras AKT/PI3-K
NFB
Bcl-2
TNF-
MDR1
Chemo-Resistance
SurvivalProliferation
ATMP
ATMP
Mutant p53
Substratephosphorylation
ATMP
Nbs1P
ATM PBrca1P
p21 waf1/cip1
DNA Repair
Focus Formation
Induced RadiationResistance
LDFRTdirectly activates
Collaborators and the Lab
Dr Mohiuddin, Director, Geisinger-Fox Chase Cancer