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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.
Radiation Cell Survival Curve: Redefining ‘the shoulder’
Radiation Cell Survival Curve: Redefining ‘the shoulder’
Preclinical data suggest
that LDFRT (<1 Gy) potentiates the effectiveness of various chemoRx agents including Taxol, Cisplatin, and Gemcitabine
Preclinical data suggest
that LDFRT (<1 Gy) potentiates the effectiveness of various chemoRx agents including Taxol, Cisplatin, and Gemcitabine
HYPER-RADIATION SENSITIVITY
• HRS was documented in more than 40 tumor cell lines in response to single low dose radiation
• HRS occurs after fractionated low-doses in in-vitro
• Increased HRS is observed in G2M cell cycle phase
• HRS does not exhibit cellular repair mechanisms
Traditional Dose Time Fractionation (2 Gy/ day)
Low Dose/fraction (0.5 Gy b.i.d/day)
M T W T F
M T W T F
M T W T F
M T W T F
M T W T F
M T W T F
M T W T F
M T W T F
M T W T F
M T W T F
M T W T F
M T W T F
USE OF HRS INDUCING DOSE IN CLINIC?
Can HRS-inducing low-dose radiation potentiate the
effect chemotherapy?
LDFRT, potentiator of Taxanes
20181614121086420
T+2Gy
T+1 Gy (2 x) ��
T+0.5 Gy (4x)
4.053571429
5.279069767
4.509933775
1.666666667
2.679558011
3.927125506
2.4
3
10
0.915254237
1.35
2.571428571
4.923076923
5.565217391
12.8
HCT-116
HT-29
SCC61
SQ20B
2774
Taxane chemo-potentiation Enhancement Ratio
Treatments
LDFRT, potentiator of Gemcitabine
43210
Gemzar+2 Gy
Gemzar+1Gy (2 x)
Gemzar+0.5Gy (4x)
1.234756098
1.117241379
1.157142857
1.63559322
1.676935229
3.10380117
PANC-1MIA PaCa-2
GEMZAR Chemo-potentiation Enhancement Ratio
Treatments
LDFRT, potentiator of Cisplatin
14121086420
C + 2 Gy
C + 1 Gy (2x)
C + 0.5 Gy (2x)
4.4
4.967741935
5.310344828
2.394009217
3.42226614
3.055882353
4.180327869
10.51546392
6.455696203
2774
H157
UKY29
Cisplatin Enhancement ratio
Treatments
LDFRT impede the activation of NFB, NFY1 and ERE function
SCC-61
LDFRT impede the activation of NFB, NFY1 and ERE function
SQ20B
LDFRT impede the activation of NFB, NFY1 and ERE function
SQ20B
LDFRT impede the activation of NFB, NFY1 and ERE function
BG1
Targets of NFB and NFY1 (mdr-1 and bcl-2) are not up-regulated in response to LDFRT
T-167
TACTGGGAATTCTCAATG------GAGGCTGATTGGCTGGGC--hMDR1NFB
NF-YA NF-YB
NF-YC
-6092 -6083 -82 -72
LUC
+1 +162
MDR-1 and LDFRT : NF-Y link
Bcl-2 and LDFRT : NFB link
SQ20B
SCC-61
Chemopotentiating effect of LDFRT in in-vivo
Chemopotentiating effect of LDFRT in in-vivo
LDFRT in the clinic
Low-dose Fractionated Radiation (LDFRT) as a potentiator of neoadjuvant Paclitaxel
(P) and Carboplatin (C) in Locally Advanced Squamous Cell Carcinoma of the
Head and Neck (SCCHN).
S. Arnold, M. Kudrimoti, J. Valentino, P. Spring, M. Ahmed, W. Regine, D. Kenady, C. Given, M. Mohiuddin
Supported in part by an unrestricted research grant from Bristol-Myers Squibb
Treatment Schema: Trial 1
Response assessment
2 cycles
q 21d
Taxol 225 mg/m2Carboplatin AUC=6
80 cGy
Day 1 Day 2
Definitive surgery or radiation
80 cGy
80 cGy
80 cGy
Arnold, et al. Abstract #1112
Treatment Schema: Trial 2
Response assessment
Day 8
Taxol 75 mg/m2Carboplatin AUC=6 Days 1, 2
Taxol 75 mg/m2
Definitive surgery or radiation
Day 1550 cGy
Taxol 75 mg/m2
2 cycles q 21d
50 cGy
50 cGy
50 cGy
50 cGy
50 cGy
50 cGy
50 cGy
Arnold, et al. Abstract #1112
Grade 3 and 4 Toxicities
Toxicity Trial 1 (n=39) Trial 2 (n=16)
Neutropenia 50% 25%
Infection 13% 5%
Dermatitis 8% 0%
Pulmonary 3% 0%
Allergic 3% 0%
Diarrhea 0% 6%
Arthralgias/Myalgias 3% 0%
Allergic 3% 0%Arnold, et al. Abstract #1112
Trial Response n CR (%) PR (%) SD (%) PD (%) RR (%)
Trial 1 Primary Site 39 11 (28%) 24 (62%) 4 (10%) 0 35 (90%)
Overall 39 5 (13%) 27 (69%) 6 (15%) 1 (3%) 32 (82%)
Trial 2 Primary Site 16 10 (63%) 5 (31%) 1 (6%) 0 15 (94%)
Overall 16 6 (38%) 8 (50%) 2 (12%) 0 14 (88%)
Arnold, et al. Abstract #1112
Results: Trials 1 & 2
Conclusions
Chemopotentiating LDFRT combined with Paclitaxel and Carboplatin is effective in SCCHN and has a similar toxicity to chemotherapy alone
RR was 82% in Trial 1 and 88% in Trial 2 Primary site CR rate improved from 28% in Trial 1 to 63%
in Trial 2 This primary site CR rate is comparable to the highest
reported CR rate in induction therapy with considerably less side effects, and may have a significant impact on long-term outcome
Arnold, et al. Abstract #1112
PANCREAS CANCERPANCREAS CANCER
STRATA A – Locally advanced/metastatic (Liver) GI Tumors without Peritoneal Carcinomatosis: LD-UART off GEMCITABINE off Repeat q 21 days [4 cycles
total] DAY 1,2 8,9 15 LD-UART - Low dose Upper Abdominal Radiation Therapy - 60 cGy (initial), 70,
80, 90 (bid x 2 days)Gemcitabine: 1250 mg/m2 over 2 hours.
STRATA B - As above but with Peritoneal Carcinomatosis: LD-WART off GEMCITABINE off Repeat q 21 days [4 cycles
total] DAY 1,2 8.9 15 LD-WART - Low dose Whole Abdominal Radiation Therapy – 60cGy (initial), 70, 80, 90
(bid x 2 days) Gemcitabine: 1250 mg/m2 over 2 hours.
Patient Characteristics (n=10)
Patient Characteristics (n=10)
Median Age: 60 years (49 - 82)
Tumor Type/Number: Unresectable Pancreas 5 patients
Metastatic Pancreas (Liver) 4 patients
Unresectable Small Bowel 1 patient
Prior Therapy: 1 patient
Median Age: 60 years (49 - 82)
Tumor Type/Number: Unresectable Pancreas 5 patients
Metastatic Pancreas (Liver) 4 patients
Unresectable Small Bowel 1 patient
Prior Therapy: 1 patient
Radiographic Responses (n=10)
Radiographic Responses (n=10)
Radiographic Response by RECIST Criteria:1 CR (10%)2 PR (20%)5 SD (50%)2 PD (20%)
* Median survival for all 10 patients is 10 months
(range 4 - 37).
Radiographic Response by RECIST Criteria:1 CR (10%)2 PR (20%)5 SD (50%)2 PD (20%)
* 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
Center,Wilkes-Barre, PA
Dr Paul Spring, Associate Professor,
Department of Otolaryngology, University of
Arkansas Medical Center, Little Rock,
AR
Dr Susanne Arnold, Associate Professor,
Department of Internal Medicine
(Hem -Onc), University of
Kentucky Medical Center, Lexington, KY