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Mansoor M. Ahmed PhD Staff Scientist biologyofcancer

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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Mansoor M. Ahmed PhD Staff Scientist biologyofcancer

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  1. 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

  2. Low-dose fractionated radiation as a chemo-potentiator

  3. 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.

  4. 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

  5. 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

  6. USE OF HRS INDUCING DOSE IN CLINIC? Traditional Dose Time Fractionation (2 Gy/ 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 Low Dose/fraction (0.5 Gy b.i.d/day)

  7. Can HRS-inducing low-dose radiation potentiate the effect chemotherapy?

  8. LDFRT, potentiator of Taxanes

  9. LDFRT, potentiator of Gemcitabine

  10. LDFRT, potentiator of Cisplatin

  11. LDFRT impede the activation of NFkB, NFY1 and ERE function SCC-61

  12. LDFRT impede the activation of NFkB, NFY1 and ERE function SQ20B

  13. LDFRT impede the activation of NFkB, NFY1 and ERE function SQ20B

  14. LDFRT impede the activation of NFkB, NFY1 and ERE function BG1

  15. Targets of NFkB and NFY1 (mdr-1 and bcl-2) are not up-regulated in response to LDFRT

  16. T-167 MDR-1 and LDFRT : NF-Y link -82 -72 +1 +162 -6092 -6083 NF-YA NF-YB TACTGGGAATTCTCAATG------GAGGCTGATTGGCTGGGC-- hMDR1 LUC NFkB NF-YC

  17. Bcl-2 and LDFRT : NFkB link SCC-61 SQ20B

  18. Chemopotentiating effect of LDFRT in in-vivo

  19. Chemopotentiating effect of LDFRT in in-vivo

  20. LDFRT in the clinic

  21. 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

  22. Treatment Schema: Trial 1 Taxol 225 mg/m2 Carboplatin AUC=6 80 cGy 80 cGy 80 cGy 80 cGy Day 1 Day 2 Definitive surgery or radiation 2 cycles q 21d Response assessment Arnold, et al. Abstract #1112

  23. Treatment Schema: Trial 2 Taxol 75 mg/m2 Carboplatin AUC=6 50 cGy 50 cGy 50 cGy 50 cGy Days 1, 2 Taxol 75 mg/m2 50 cGy 50 cGy Day 8 50 cGy 50 cGy Day 15 Taxol 75 mg/m2 2 cycles q 21d Definitive surgery or radiation Response assessment Arnold, et al. Abstract #1112

  24. Grade 3 and 4 Toxicities Arnold, et al. Abstract #1112

  25. Results: Trials 1 & 2 Arnold, et al. Abstract #1112

  26. 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

  27. PANCREAS CANCER

  28. 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.

  29. 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

  30. 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).

  31. Pre Treatment Post Treatment

  32. Pre Treatment Post Treatment

  33. Conclusions • 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

  34. Future 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 ofOpportunity • Colorectal CA (FOLFOX) rFOLFOX • Hodgkins Lymphoma (ABVD) rABVD • NHL (CHOP) rRCHOP • Breast Cancer (CMF) rAC-T • Ovarian (Taxotere) rTaxotere • H&N (CarboTaxol) rCarboTaxol • Etc..

  35. Ionizing radiation Chromatin changes ATM ATM Autophosphorylation DNA Repair Reactive Oxygen Species Focus Formation P ATM P P P Substrate phosphorylation p21 waf1/cip1 G1 Arrest ATM ATM ATM EGR-1 p53 P Bax Cell Death Ras AKT/PI3-K TNF-a Activation Caspases NFkB P Nbs1 MDR1 Bcl-2 P Brca1 ATM P Chemo- Resistance Survival Proliferation DNA repair process is not activated by LDFRT

  36. LDFRT directly activates ATM ATM P Ionizing radiation Brca1 ATM Chromatin changes Autophosphorylation P P P ATM DNA Repair P P Nbs1 ATM ATM Reactive Oxygen Species Focus Formation Substrate phosphorylation p21 waf1/cip1 Mutant p53 Bax Ras AKT/PI3-K TNF-a NFkB Induced Radiation Resistance MDR1 Bcl-2 Chemo- Resistance Survival Proliferation

  37. 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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