Download Localized Chemo-Radiation for Prostate Cancer Graduate Interdisciplinary Topics PhD in Bioengineering

Graduate
Interdisciplinary Topics
PhD in Bioengineering
Abstract ID# 1310
Localized Chemo-Radiation for Prostate Cancer
Jodi Belz1, Rajiv Kumar1,3, Houari Korideck3, Robert Cormack3, Mike Makrigiorgos3, Srinivas Sridhar1,3
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Nanomedicine Science and Technology Center, 2 Northeastern University, Boston, MA 02115 3Department of Radiation Oncology, Dana Farber Cancer Institute, Brigham and Women’s Hospital, Harvard
Medical School, Boston, MA.
Prostate cancer is the second leading cause of cancer related deaths in men. While 5year survival rates are high, prostate cancer is slow-growing and recurring tumors that
are often unresponsive to treatment. Salvage brachytherapy offers a second chance for
cure but leads to high rates of rectal toxicity. We aim to locally radiosensitize the
prostate throughout the duration of brachytherapy treatment to enable the use of
lower radiation doses with lower toxicities for a greater chance of cure.
Currently, brachytherapy uses inert spacers for spatial guidance during the one-time
injection of radioactive seeds. We leverage the use of these spacers to create a new
modality of chemo-radiation therapy, replacing the spacers routinely used in
brachytherapy with biodegradable spacers doped with radiosensitizing drug
(docetaxel). This approach provides localized in-situ delivery of the chemotherapeutic
sensitizer directly to the tumor and avoids the toxicity associated with current systemic
delivery. This work presents a biodegradable spacer loaded with docetaxel and inserted
intratumorally in mice as a monotherapy as well as combined with radiation for local
chemo-radiotherapy. As a monotherapy, in vivo efficacy of the localized spacer versus
the standard systemic dosing was tested. The therapeutic benefit of spacer proved to
be significantly greater with fewer toxicities than standard clinical treatment. The
localized chemo-radiosensitizer was then combined with radiotherapy to demonstrate
a synergistic effect at lower doses. The combined treatment showed the highest degree
of tumor suppression with significant growth inhibition by day 90. This work
demonstrated clinical promise for high therapeutic benefit and lower toxicities.
PC3 Xenographed Athymic Nude Mouse Model (n=10/group)
One-time Docetaxel dose ~ 36 mg DTX/kg mouse (MTD~40mg/kg)
• Preliminary Hematology and Blood Chemistry
show no spacer associated toxicities.
• LCT showed significant tumor suppression vs.
control and comparable IV dose.
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Prostate cancer (PCa) is 2nd leading cause of cancer related deaths in men
220,800 new cases (53K localized PCa) and 27,540 deaths estimated in the US in 2015.
20-30% chance of relapse with recurrence:
high toxicities from added treatments with higher chance of tumor resistance.
89% mouse survival treated with spacers vs.
0% survival for all other groups at day 40.
PC3 Xenographed Athymic Nude Mouse Model (n=3/group)
Docetaxel dose ~ 18 mg DTX/kg mouse
Localized Chemo-Radiation Therapy (LCRT) aims to radiosensitize the tumor site to
decrease systemic toxicities and increase chance of cure.
SEM Images of Flash Frozen INCeRT Spacers
Sustained radiosensitization for entirety of
brachytherapy by the DTX slowly released from
the INCeRT spacer (blue line) compared with
intermittent
radiosensitization
from
IV
administration of DTX.
• No observable toxicity
• LCT & LCRT inhibits growth and shrinks tumor as DTX is released from spacer.
• Average survival rate for the non treated mice was 40 days as opposed to treated
(Chemo+Rad) mice which are still alive at 140 days time point.
Combined local chemo-radiation (LCRT) approach showed best tumor regression as
compared to other treatment groups.
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Designed to be injected in conjunction with current brachytherapy outpatient procedure
for no additional discomfort to patient.
Release of DTX optimized to have sustained therapeutic dose in tumor throughout course
of radiation for constant radiosensitization.
FDA approved components for easy translation into clinic.
Robust INCeRT (ImplaNtable Chemo-Radiation Therapy) platform can utilize technology for
various drugs to treat many cancers.
1. Kumar, R., Belz, J., Markovic, S. et al Int J Radiation Oncol Biol Phys 91:393-400, 2015.
2. Cormack, R.A., Sridhar, S., Suh, W.W., et al Int J Radiat Oncol Biol Phys 76:615-23, 2010.
3. Nagesha, D.K., Tada, D.B., Stambaugh, C.K., et al Phys Med Biol, 55:6039-52, 2010
Supported by IGERT grant NSF-DGE- 0965843 and ARMY/ W81XWH-12-1-0154 and by Brigham and Women’s Hospital.