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Current Research Projects Using the Molecular Imaging Center Resources
Funded
Projects
- [F-18] paclitaxel: an in vivo marker
for MDR in tumors
Principal Investigator: Karen
A. Kurdziel, MD
Co-Investigators: Radiology: Jerry I. Hirsch, PharmD,
MSc; Joseph D. Kalen, PhD, MSHA; John D. Wilson, PhD
Sponsor: (1R21 CA098334-01) National Cancer Institute
8/01/03 - 8/01/05 $375,000 Total Award (Direct + Indirect)
Collaborators: W. Eckelman, PhD, PET Department,
Imaging Sciences Program, and M. Gottesman, MD, Laboratory of Cell
Biology, National Cancer Institute, NIH
Abstract: Over-expression of the membrane pump P-glycoprotein
(Pgp) results in multidrug resistance (MDR), a common cause of cancer
treatment failure. Pgp actively removes drugs from the tumor cells.
Paclitaxel is a commonly used chemotherapeutic agent, and MDR often
complicates its use. The PET department at the NIH has developed an
efficient radiosynthesis for [18F] paclitaxel (F PAC), which is a
substrate of the Pgp pump. Because [18F] is a positron emitter, the
in vivo kinetics of FPAC can be measured using positron emission tomography
(PET). It is expected that, by measuring the kinetics of FPAC in tumors,
the function of Pgp in vivo can be estimated. This proposal intends
to obtain preliminary evidence that FPAC PET biodistribution and PET
kinetic imaging parameters correspond to the measured expression of
Pgp in a mouse xenograft model.
- Early Clinical Trials of New Imaging
Agents
Principal Investigator: Karen
A. Kurdziel, MD
Core Investigators: School of Pharmacy: W. Barr,
PhD, PharmD
Radiology: P. Fatouros, PhD; J. Hirsch, PharmD MSc; J. Kalen, PhD
MSHA;
J. Wilson, PhD; K. Schmidt
Sponsor:
Biomedical Imaging Program, NCI (N01-CM-27165-45)
9/30/02 - 9/30/07 $2,245,168 Total award (Direct + Indirect)
This contract will utilize a Core Interdisciplinary Network (CIN),
comprising resources from the Schools of Medicine (Massey Cancer Center,
Radiology, GCRC, Molecular Diagnostics), Pharmacy (Center for Drug
Studies and Medicinal Chemistry), and Humanities and Science (Chemistry).
Other investigators will be recruited based on the specific needs
of the RFPs offered.
- Preliminary evaluation and human dosimetry
of [F-18] paclitaxel as an in vivo PET tracer for multidrug resistance
Principal Investigator: Karen
A. Kurdziel, MD
Co-Investigators:
Surgical Oncology, Harry Bear MD PhD
Radiology: Jerry Hirsch, PharmD; Joseph Kalen, PhD; John Wilson, PhD
Sponsor: Massey Cancer Center Pilot Funds $30,000
Abstract:
Multidrug resistance (MDR) is a common cause of chemotherapeutic
failure. Several MDR modulating drugs, which should make it possible
to reverse a tumor’s resistance, are currently under development.
However, at present, there are no standardized, pre-treatment, in
vivo methods for determining whether a tumor exhibits MDR.
The PET department at the NIH has developed a promising
PET agent for the evaluation of multidrug resistance: [18F] labeled
paclitaxel (FPAC). Its biodistribution was studied in rats and mice.1
Human radiation dosimetry estimates were made based on biodistribution
of FPAC in non-human primates. Using a Pgp modulator, XR9576 (QLT),
FPAC PET was used to image in vivo and quantify Pgp inhibition in
normal tissues of rhesus monkeys.2,3 Based on these initial studies,
RDRC guidelines allow 7mCi of FPAC to be administered to patients
(up to 3 studies/year); however, for IND submission, dosimetry studies
in humans are required. Although my current NCI R21 enables me to
study FPAC in a mouse xenograft model, demonstrating clinical translatability
for a proposed R01 (clinical trial with FPAC) submission will require
preliminary patient studies with FPAC. This study is a pilot study
of FPAC in 3 normal volunteers (for human dosimetry calculations)
and in 3 breast cancer patients eligible for neoadjuvant chemotherapy.
The objectives of this protocol focus on calculation of human dosimetry
estimates and on preliminary evaluation of FPAC efflux kinetics
in primary breast tumors. The results of the kinetic analysis will
be compared to the clinical therapeutic response rate (clinical
complete response) and Pgp assay of the diagnostic biopsy material.
Support Requests Submitted
- Request to the DCIDE
program (Biomedical Imaging Program, NCI) for performing the preclinical
animal toxicology studies on [F-18] paclitaxel, needed to submit an
IND application.
Principal Investigator: Karen
A. Kurdziel, MD
Sponsor: No funding payable to the University.
Request for performance of studies and provision of data needed for
IND application. Submitted August 2002. Request pending submission
of human FPAC image data.
Applications in Progress/
Other Projects
- [F-18] paclitaxel as an in vivo PET
tracer for multidrug resistance: translation to human studies
Principal Investigator: Karen
A. Kurdziel, MD
Co-Investigators:
Surgical Oncology: Harry Bear MD PhD
Radiology: Jerry Hirsch, PharmD, MSc; Joseph Kalen, PhD, MSHA; John
Wilson, PhD
Proposed Sponsor: R01 NCI
- Prostate Clinical Trial Development
Award:
Multimodality image-guided HDR/IMRT in prostate cancer: combined molecular
targeting using nanoparticle MR, 3D MRSI, and 11C acetate PET imaging
Principal Investigator: Karen
A. Kurdziel, MD
Co-Investigators:
Radiation Oncology: Jefferey Williamson, PhD, Michael Hagan,
MD PhD
Sponsor: Department of Defense (DOD) $99,500 (Direct
+ Indirect) July 2004-July 2005
Abstract:
BACKGROUND
The current standard of care in patients with prostate cancer of intermediate
risk (>15% risk of lymph node involvement) is local radiation therapy
to the primary tumor and regional pelvic lymph nodes. Unfortunately,
the use of high dose radiation in regional lymph nodes is significantly
limited by both proximity of bowel and uncertainty in identifying
involved lymph nodes. To date, the limitations of available imaging
techniques and the morbidity of pelvic irradiation place constraints
on effective lymph node basin treatment.
Molecular Targeting: This proposal utilizes 3 new molecular imaging
techniques: C-11 acetate Positron Emission Tomography (PET), ultrasmall
superparamagnetic iron oxide (USPIO) magnetic resonance (MR) imaging,
and magnetic resonance spectroscopy (MRS).
The most common PET agent, F-18 fluorodeoxyglucose
(FDG), has proven useful in many cancers, but it has limited utility
in prostate cancer because it does not uptake significantly until
the cancer becomes androgen independent. In contrast, C-11 acetate
(AC), an alternative PET agent, has shown intense uptake in tumors
(prostate, renal and liver) that have characteristically been difficult
to image with FDG. In addition, AC is excreted by the pancreas,
which enables imaging of the pelvis without confounding bladder
activity.
Nanoparticle MR imaging agents accumulate in the
lymphatic system and are able to differentiate tumor-involved lymph
nodes from normal lymph nodes with high sensitivity and specificity.
Using USPIO nodal MR imaging, tumor-involved nodes can be identified
and directly targeted with higher radiation doses. These agents
have also shown the ability to delineate the tumor/normal tissue
interface based on accumulation in reactive lymphocytes.
MR spectroscopy is likewise being used to better
localize the tumor extent within the prostate. The MRS "chemical
map" and the USPIO reactive border can be used to guide brachytherapy
seed placement.
INTERVENTION
The proposed protocol will include a combination of two new techniques:
high dose-rate brachytherapy (HDR) and intensity-modulated external
beam radiation therapy (IMRT). This particular combination delivers
high radiation dose to the prostate as well as the proximal seminal
vesicles, peri-prostatic tissues and regional lymph nodes. This
combination therapy is currently being tested in a phase I/II study
at VCUMC.
Combining HDR with IMRT reduces the morbidity associated with conventional
3D conformal therapy. Moreover, each radiation component can conform
separately to provide local "boosting" based on the molecular
imaging data. The protocol to be developed will extend beyond the
current phase I/II HDR/IMRT trial to include image-guided local
boosting of the routinely prescribed radiation doses using stereotactic
IMRT and HDR in the lymph nodes and prostate respectively. We expect
this approach both to be well tolerated and to reduce loco-regional
recurrences.
In the proposed clinical trial, radiation treatment
planning (RTP) will be based on the USPIO MR nodal imaging and MRS,
which are the most established molecular targeting modalities for
the lymph nodes and prostate respectively. This approach will enable
better targeting and delivery of higher doses of radiation to known
disease sites. RTP will also be performed using AC PET data within
the prostate and regional lymph nodes and using the USPIO MR in
the prostate. These RTP schemas will be analyzed for concordance
with each other and with those used for treatment. If concordant,
it may indicate that a single modality/imaging agent is sufficient
for targeting. In the case of discordance, further study will be
needed to validate the discrepancies in disease localization.
TRIAL DESIGN
We plan to develop a Phase I/II study of combined IMRT/HDR therapy
in patients with intermediate-risk prostate cancer that includes increased
HDR brachytherapy/ stereotactic IMRT dosage in areas of disease localized
by molecular imaging techniques. The phase I endpoint will be the
incidence of grade 3 toxicities compared with that of standard treatment.
A phase II endpoint will be achievement and maintenance of a decrease
in prostate specific antigen (PSA) levels as an indicator of local
tumor control. Estimated enrollment is 50 patients over a 3-year period.
RELEVANCE
The overall goal of the proposed clinical trial is to combine the
power of several promising molecular targeting and innovative radiation
treatment modalities into a comprehensive prostate phase I/II therapy
trial. In doing so, we will use state-of-the-art imaging to target
prostate cancer at the molecular level and treat with emerging new
image-directed radiation therapy techniques. Although these technologies
are emerging and are currently available at only a few academic institutions,
if the combination of techniques proves successful, global implementation
is feasible within the next 3-5 years. It is also possible that a
single imaging modality may prove superior in disease localization,
thus decreasing the complexity. The National Cancer Institute currently
has both the USPIO imaging agent and AC in their process to facilitate
FDA approval. Setups for performing stereotactic IMRT outside the
brain are being developed and will likely become standard of care.
This proposed effort will allow us test the clinical
application of newly developed imaging and treatment delivery techniques
combined to permit safer and more effective irradiation of patients
who are likely harboring larger tumor burdens than have been controlled
via standard radiation and radiation planning techniques.
- Optimization of Rb-82 Cardiac PET for
routine clinical application
Principal Investigator:Karen
A. Kurdziel, MD
Co-Investigators:Radiology: Joseph Kalen PhD, MSHA;
Jim McCumiskey,BS, CNMT,PET; George Francis (Bioengineering Graduate
Student), Michael Kontos MD (Division of Cardiology)
Funding:Bracco Diagnostics $30,000 Direct
- Human
dosimetry estimates of C-11 DHA
Principal Investigator: Karen
A. Kurdziel, MD
Co-Investigators:Radiology, Geoffrey
Fey, MD;
NIH: Peter Herschivotch, MD (PET, CC); John C. Umhau, M.D. (LCS, NIAAA),
Michael Channing, Ph.D., (PET, CC); Norman Salem, Jr., Ph.D., (LMBB,
NIAAA)
Proposed Funding: None at present, but this work
is likely to lead to larger collaborative projects for which funding
can be sought.
Abstract: Docosahexaenoic acid (DHA) is a nutritionally
essential omega-3 fatty acid that is taken up by brain phospholipids
and is important for normal neuronal function. DHA deficiency occurs
in alcoholism and may result in decreased brain DHA and neuropsychiatric
deficits. In preparation for PET studies in humans, we evaluated [11C]DHA
biodistribution, kinetics and radiation dosimetry in non-human primates.
Methods: Dynamic 2D PET scans were obtained with a GE Advance tomograph
in 3 rhesus monkeys after injection of 1482-1896 MBq of [11C]DHA.
The scanner bed was repeatedly moved axially to image head, chest,
abdomen and pelvis over 2 hours. Region of interest placement was
aided by summing dynamic images to visualize tracer distribution and
by using a rotating maximum intensity projection of transverse slices
of the whole body. Residence times measured from scan data were extrapolated
to humans and radiation dose estimates were calculated with MIRDOSE
3.0. Results: Cumulative organ activities accounted for 78% of the
injected dose and whole body activity for 84%. The liver, myocardium,
and kidneys received the highest radiation doses, 0.029 mGy/MBq (0.107
rad/mCi), 0.0098 mGy/MBq (0.036 rad/mCi), and 0.0062 mGy/MBq (0.023
rad/mCi), respectively. The effective dose equivalent is 0.0038 mSv/MBq
(0.014 rem/mCi). There was early accumulation of activity in liver
and kidneys, neither of which showed significant tracer clearance.
The myocardium accumulated [11C]DHA more slowly, peaking at 40-60
min. The brain accumulated less activity (0.00038mGy/MBq [0.0014 rad/mCi]).
The total activity in brain remained fairly constant following clearance
of the initial blood flow phase. Conclusions: [11C]DHA shows suitable
dosimetry for use in humans; under RDRC guidelines, up to 1728 MBq
(46.7 mCi) of [11C]DHA can be administered per study. [11C]DHA will
be useful to non-invasively study disorders of DHA metabolism by providing
a means of measuring the rate of DHA incorporation into organs.
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