novel radio-therapeutic deliveries to induce apoptosis in epithelial and endothelial compartment of...

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


SQ20B


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

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


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%)


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


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

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

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