Tripos, Inc.
1699, South Hanley Road
St. Louis MO 63144

Tel: (314) 647 1099; Email: hodgkine@tripos.com

The sequencing of the human genome provides an unprecedented opportunity for drug discovery. It is estimated that the approximately 500 drug targets currently known will grow in number to 5000 over the next decade. At the same time, high-throughput drug discovery is rapidly creating a vast knowledge of how chemical compounds interact with biological targets. Exploitation of this knowledge-base will create an understanding of how chemical space maps onto biology space and lead to highly efficient knowledge-based drug discovery. This will be enabled by technological breakthroughs in virtual representation of chemical space, design of chemical libraries and structural genomics. An approach to efficient parallel discovery for multiple targets within a gene family will be described, with examples drawn from proteases, kinases and GPCRs.

Figure
Mapping chemistry onto biology space. Examples of regions in which drugs may be found are shaded.




A New Paradigm for the Specific Delivery and Immobilization of Radio-Isotopes within Tumors for Diagnosis and Therapy of

Sam Rose, M.D.
Oncologic Inc., Richmond CA 94806

The proposed cancer therapy direction is a 4-step process that can overcome the targeting limitations of monoclonal antibodies to achieve cancer-specific delivery and retention of large numbers of radio-isotopes via a limited number of intravenous infusions/injections over a period of 5-10 days. The cornerstone of the process is a new class of proprietary chemical agents called SPRs (Soluble Precipitating Reagents), which can be radio-labeled. The SPRs are administered in soluble form and become insoluble in tumors (similarly to the iodide colloid formed in thyroid cancer therapy). The proposed therapeutic process has the capacity to replicate the therapeutic conditions achieved during the treatment of thyroid cancer for other solid cancers (breast, colon, lung, prostate, etc.) and is not defeated by tumor heterogeneity or shared characteristics between cancer and normal cells.

Step 1 – A non-toxic, trace-labeled Soluble Precipitating Reagent (SPR) which includes a non-mammalian surrogate receptor is covalently attached to a tumor-targeting ligand to form a soluble complex that circulates throughout body fluids, binds to targeted receptors, and induces receptor-mediated endocytosis and lysosomal processing. In lysosomes, the soluble SPR is cleaved from the targeting ligand and forms an insoluble, trace-labeled, stable, non-digestible precipitate with non-mammalian surrogate receptors. A large amount of this trace-labeled precipitate will accumulate in each cell over several days (1,000 times as many molecules as the number of targeted cell surface receptors), and the precipitate is retained inside cells for a very long time (weeks, instead of hours or days), allowing ample time for complete clearance of non-endocytosed complex from the blood and extravascular compartment prior to diagnostic scanning and completion of therapy.

Step 1 of the process alone should result in improved diagnostic scanning of tumors. Compared to conventional radioimmunoscintigraphy, the proposed approach will (a) be able to detect tumors containing one one-thousandth as many cells, (b) greatly enhance image contrast, because the scan can be carried out with very low background radiation in the blood and extravascular compartment, and (c) increase diagnostic specificity, because the reagent can be administered at low concentration over a long period of time, and because repeat scans can detect lesion growth and cell death.

Step 2 – A very-low dose of a currently approved chemotherapy agent is administered to kill only the small fraction of super-sensitive cancer cells which have multiple genetic and epigenetic errors (and few if any normal cells), thereby breaking them open and relocating their precipitate into the tumor extracellular space.

Step 3 – A cell-impermeant bispecific reagent is administered, comprised of a non-mammalian binding moiety which binds specifically and covalently to the non-mammalian surrogate receptors on the precipitate (which itself is only in the tumor tissue extracellular space), and a non-mammalian enzyme moiety which is used in Step 4. Because the bispecific reagent is bound covalently to the surrogate receptors on the precipitate, sufficient time can be allowed between Steps 3 and 4 for any unbound bispecific reagent to be excreted from normal tissues prior to Step 4.

Step 4 – A non-targeted therapeutically radio-labeled SPR is administered which is converted into a radioactive therapeutic precipitate ONLY by the action of the non-mammalian enzyme bound to the precipitate in the tumor extracellular space. Large numbers of radioactive therapeutic precipitate molecules are thereby localized and retained in the tumor extracellular space and cause radio-necrosis of the tumor.

The proposed approach achieves high cancer specificity by requiring a cell to have 5 cancer--associated traits (receptor positive, supersensitive, poor lymphatic drainage, inhibited macrophage activity, no exfoliation) before it is capable of immobilizing isotopes in Step 4. Even though only a fraction of all the cancer cells have ALL FIVE TRAITS (and even fewer normal cells), the Process can still eradicate ALL the cancer cells because the immobilized isotopes generate multiple overlapping fields of microregional radio-necrosis that destroy neighboring trait-negative cancer cells.




Electrical Impedance Tomography

D. Isaacson, Ph. D., J. C. Newell, Ph. D., and G. Saulnier, Ph. D.

Rensselaer Polytechnic Institute Troy, NY

Electrical Impedance Tomography systems apply small electrical currents through electrodes on the surface of a body. They record the voltages that result. This electrical data is used to reconstruct and display in real time images of the electrical conductivity and permittivity inside the body.

Since lungs filled with air have a lower conductivity than lungs with less air these systems can be used to monitor respiration. Since lungs perfused with blood have a higher conductivity than lungs with less blood inside these systems can be used for monitoring perfusion.

Recently it has been shown that many breast tumors have a significantly higher electrical conductivity and permittivity than surrounding normal tissue. For this reason Electrical Impedance measuring and imaging systems are being designed and tested to screen
for breast cancer.

Based on blinded multi-center clinical trials The T-Scan system was approved by the FDA this year to be used on those patients for whom the standard x-ray mammogram is ambiguous.

We explain how impedance tomography systems work as well as report on the design and performance of the ACT3 system developed at RPI. We explain how the goals of obtaining the greatest sensitivity and specificity have led to the design of adaptive systems.

Images and video of ventilation and perfusion made with the ACT3 system will be shown .




Three-Dimensional Computed Tomography-Guided Monotherapeutic Pararectal Brachytherapy of Prostate Cancer with Seminal Vesicle Invasion: 6-Year Folowup

Panos Koutrouvelis M.D., Niko Lailas M.D., Fred Hendricks M.D., Guillermo Gil-Montero M.D., James Sehn M.D., Stuart Katz M.D.

Uro-Radiology Prostate Institute, Vienna, Virginia

Purpose: To treat patients with prostate cancer and seminal vesicle invasion with monotherapeutic three dimensional computed tomography (3-D CT)-guided posterior pararectal brachytherapy.

Methods & Materials: Four hundred thirty four (434) patients with clinical stage T1a,b or T2a,b prostate cancer were referred for 3-D CT-guided brachytherapy. Each underwent further staging with 3-D CT-guided pararectal biopsy of the seminal vesicles under local anesthesia during pre-treatment CT-planning. Fifty two (52) patients (12.6%) were upstaged to T3c disease. In the set of 52 patients, nine (9) had Gleason’s score&Mac178; 6, thirty (30) Gleason's score = 7, and thirteen (13) patients&Mac178; 8. Initial PSA was < 10 ng/ml in 18 patients, 10-20 ng/ml in 14 patients, and >20 in 20 patients. Of the 52 patients, 47 patients were treated monotherapeutically with 3-D CT-guided brachytherapy. No patients received hormone therapy after the implant. The prescribed dosage to the seminal vesicles and prostate is 120 Gy with Pd-103 seeds and 144 Gy with I-125 seeds.

Results: The prescribed dosage was achieved in all 47 patients throughout the seminal vesicles whose range of target radiation extended 5-10 mm outside the target in the adjacent fat as calculated with post-implant CT-dosimetry with Varian BrachyVision or MMS software. Prostate Specific Antigen (PSA) outcome data were available in 37 patients treated with monotherapy and follow up ranged from 12 - 72 months (median, 36 months). Decreased PSA levels were stratified into groups based on the presenting Gleason's score and initial PSA. In the first group (Gleason's score&Mac178; 6 and initial PSA < 20 ng/ml), PSA levels decreased to less than 0.5 ng/ml in all 7 patients (100%) after brachytherapy. In the second group (Gleason’s =7 and initial PSA < 20 ng/mL), PSA levels decreased to less than 2 ng/ml in 12 of 12 patients (100%) and to less than 0.5 ng/ml in 10 of the 12 (83% in this group). In the third group (Gleason's score = 7 and initial PSA > 20 ng/ml), PSA decreased to less than 0.5 ng/ml in 7 out of 10 patients (70%). In the fourth group (Gleason's score&Mac178; 8 and initial PSA < 20 ng/mL) PSA decreased to less than 0.5 ng/mL in 3 of 4 patients (75%). In the final group (Gleason's score&Mac178; 8 and initial PSA > 20 ng/mL), PSA decreased less than 0.5 ng/mL in 2 out of 4 patients (50%).

Conclusion: 3-D CT-guided monotherapeutic brachytherapy delivers adequate dosage to the seminal vesicles. Clinical and biochemical results are encouraging in patients with low initial PSA levels regardless of their Gleason's scores, but longer-term data in a greater number of patients is necessary.




CT Screening for Lung Cancer

David Yankelevitz MD., Department of Radiology
Weill Medical College at Cornell, The New York Presbyterian Hospital


Lung cancer accounts for the highest number of cancer deaths both in the United States and worldwide. It is highly curable when found in its earliest stages and is highly fatal when found in an advanced stage. Nevertheless, no screening examination is currently recommended for its early detection as previously performed randomized controlled trials failed to show a decrease in the mortality rate. Upon reanalysis of these studies it has been found there were serious flaws which could easily account for the failure to show a benefit of screening. In this presentation issues related to screening in general will be discussed. A new paradigm for the evaluation of screening will be presented. The conceptual framework for the paradigm is that the purpose of screening is
early diagnosis and that screening should be evaluated in terms of how early the diagnosis is made under a particular screening regimen. The cancers found under this regimen of screening will then be followed to determine the cure rate. By studying a new test for screening in this manner, many of the pitfalls previously encountered when evaluating a diagnostic screening test can be avoided.