| dc.description.abstract |
<p>Radiation therapy (RT) has been a standard-of-care treatment for many localized
cancers for decades. Despite being an effective treatment modality for many clinical
presentations, the efficacy of RT against cancer can be limited due to local recurrence,
metastatic spread, and radiation resistance from tumor hypoxia. These limitations
provide opportunity for innovative approaches to enhance the overall efficacy of RT.
This thesis explores the potential novel approach to enhancing RT through the paradigm
changing approach of adding a phototherapeutic component initiated simultaneously
with RT. X-ray Psoralen Activated Cancer Therapy (X-PACT) is one such approach, where
diagnostics-energy kilovoltage (kV) x-ray coupled with energy modulators (phosphors)
converts kV photon to ultraviolet (UV) light, which in turn activates psoralen. Radiotherapy
Enhanced with Cherenkov photo-Activation (RECA) is another approach, where therapeutic
megavoltage (MV) x-ray generates UV light via Cherenkov phenomenon. Both approaches
could increase local control in RT, increase treatment effectiveness in hypoxic tumors,
and amplify anti-cancer systemic response. The overarching hypothesis that drives
this dissertation is that X-PACT and RECA can activate psoralen to enhance cytotoxicity
in-vitro and tumor growth control in-vivo compared to RT alone. In line with this
hypothesis, this work explores the feasibility of both X-PACT and RECA via in-vitro
and in-vivo verification as well as optimization of radiation techniques to maximize
the therapeutic benefit of the approach.</p><p> X-PACT and RECA in-vitro / in-vivo
studies indicate radiotherapy enhancement is plausible with psoralens activated by
secondary UV light production from radiation, though further investigation is required
to establish feasibility of RECA in-vivo. For X-PACT in-vitro, a substantial reduction
in cell viability and increase in apoptosis was observed in various murine cancer
cells (4T1, KP-B, and CT2A) when treated with a combination of 50µg/mL phosphor, 10µM
psoralen (8-MOP), and 1Gy of 80kVp x-ray (viability < 20%), compared to any of these
components alone (viability > 70%). This suggests a synergistic interaction between
the components congruent with the X-PACT scheme, where x-ray induces phosphor UV emission,
which in turn activates psoralen. The X-PACT in-vivo mice study showed improved survival
with X-PACT versus saline control with flank 4T1 tumors (30.7 days for X-PACT vs.
21.6 days for saline) for survival criteria of 1000, 1500, and 2000mm3, respectively.
For RECA, in-vitro results seem promising, where reductions in viability of 20% and
9.5% were observed for 4T1 and B16 murine cancer cell lines treated with RECA (radiation
+ trioxsalen, a potent psoralen derivative) versus radiation alone. A substantial
increase in MHC I expression was observed for B16 cells treated with RECA versus those
treated with radiation alone. A small RECA in-vivo pilot study using 8-MOP was inconclusive.
Further in-vivo trials with a greater number mice per arm of are required to establish
the RECA feasibility to enhance radiotherapy.</p><p> Feasibility of treatment optimization
for both X-PACT and RECA were demonstrated with kV and MV beams respectively, by optimization
of optical output per radiation dose delivered. It was found that in both X-PACT and
RECA scheme, the energy of the photon radiation beam (i.e. tube voltage and LINAC
energy settings) affected optical output the most. With kV beams for X-PACT, accurate
beam delivery within the target volume to reduce normal tissue damage typically expected
of kV beams was demonstrated with a 3D-printing-based preclinical irradiation scheme,
which is expected to help X-PACT translation into the clinics. In addition, for X-PACT,
novel MV-responding phosphors were characterized under MV radiation beam, suggesting
the possibility of MV-radiation-mediated X-PACT. Immediate future studies should investigate
the efficacy of the optimized X-PACT and RECA, as well as MV X-PACT in-vitro and in-vivo.
Studies beyond these immediate ones should investigate X-PACT and RECA efficacy against
hypoxic and metastatic tumor sites, where radiation can traditionally fail.</p>
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