Development of a voided urine assay for detecting prostate cancer non-invasively: a pilot study

This publication has validated the Thomas Jefferson University hypothesis that prostate cancer can be detected non-invasively by a simple and reliable assay by targeting genomic VPAC receptors expressed on malignant prostate cancer cells shed in voided urine.

Development of a voided urine assay for detecting prostate cancer non-invasively

Edouard J. Trabulsi*, Sushil K. Tripathi†, Leonard Gomella*‡, Charalambos Solomides§, Eric Wickstrom‡¶ and Mathew L. Thakur†‡ Departments of *Urology, The Sidney Kimmel Cancer Center, Thomas Jefferson University, Philadelphia, PA.

VPAC1 Targeted 64Cu-TP3805 kit preparation and its evaluation

The Laboratories of Radiopharmaceutical Research and Molecular Imaging at Thomas Jefferson University have previously shown that 64Cu-TP3805 can specifically target VPAC1 receptors and can be used for positron emission tomography (PET) imaging of breast (BC) and prostate cancer (PC) in humans.

Availability of ready to use N2S2-peptide kits for 64Cu labeling is convenient and eliminates possible day to day variation during its routine preparation for clinical use.

Authors: Sushil K Tripathi, Pardeep Kumar, Edouard J Trabulsi, Sung Kim, Peter A McCue, Charles Intenzo, Adam Berger, Leonard Gomella, Mathew L Thakur Nucl Med Biol 2017 Aug 3;51:55-61. Epub 2017 May 3. Thomas Jefferson University, Department of Radiology; The Sidney Kimmel Cancer Center. Electronic address: August 2017

VPAC1 Receptors for Imaging Breast Cancer: A Feasibility Study

This feasibility study demonstrated the compelling need for an innovative approach that would decrease the number of unnecessary benign biopsies while still detecting the malignancies. A high percentage of the breast biopsies that were performed in the United States have resulted in a benign diagnosis. These unnecessary biopsies create significant patient morbidity and potentially unnecessary health care costs. To detect BC, digital mammography, MRI, CT, sonography, 18F-FDG, and 99mTc-sestamibi have made significant advances.

However, these modalities have limited specificity, and all continue to produce many false-positive and false-negative results (3–12). At an average cost of $5,000–$6,000 for each biopsy, unnecessary benign biopsies represent a serious health care burden.

VPAC1 Targeted 64Cu-TP3805 Positron Emission Tomography Imaging of Prostate Cancer: Preliminary Evaluation in Man

The feasibility study of 25 patients who underwent PET imaging, 212 prostate gland lesions had SUVmax > 1.0 vs 127 lesions identified by histology of biopsy tissues. The status of the additional 85 PET identified prostate lesions remains to be determined. In 68 histologic slides from 6 PET imaged patients, DAR (Digital Autoradiography) identified 105 of 107 PC foci, 19 of 19 high-grade prostatic intraepithelial neoplasias, and ejaculatory ducts and verumontanum involved with cancer. Additionally, DAR found 9 PC lesions not previously identified histologically. The positive and negative lymph nodes were correctly identified, and in 3 of 3 benign prostatic hyperplasia patients and 5 of 5 cysts, DAR was negative.

This study demonstrated that 64Cu-TP3805 delineates PC in vivo and ex vivo, provided normal images for benign masses, and is worthy of further studies.

99mTcLabeled Vasoactive Intestinal Peptide Analog for Rapid Localization of Tumors in Humans

In recent years, imaging tumors with receptor-specific biomolecules has been the focus of increasing interest. Vasoactive intestinal peptide (VIP)(VPAC) has a high affinity for specific receptors that are expressed in high density on many malignant tumors.

PET Imaging of VPAC1 Expression in Experimental and Spontaneous Prostate Cancer

The primary screening methods for PC are prostate-specific antigen measurement and digital rectal examination (3). However, the reported sensitivity for digital rectal examination is only 55%–68%. For prostate-specific antigen, the specificity is limited because men with benign disease such as prostatic hypertrophy and prostatitis present with elevated levels of the antigen. Its positive predictive value in asymptomatic men has been reported to be only 28%–35%. This predictive value is marginally increased to 49% if prostate-specific antigen estimation is combined with the results of digital rectal examination.

In recent years, PET has emerged as a sensitive modality for imaging oncologic lesions. For PET imaging of PC, such metabolic and biochemical agents as 18F-FDG, 11C-acetate, 18F-acetate, 11C-methionine, 11C-choline, 18F-choline, and 16b-18F-5a-dihydrotestosterone have been investigated.

Vasoactive Intestinal Peptide/Pituitary Adenylate Cyclase-activating Peptide Receptor Subtypes in Human Tumors and Their Tissues of Origin

The evaluation of peptide receptors in man is needed not only to discover the physiological target tissues of a given peptide but also to identify diseases with a sufficient receptor overexpression for diagnostic or therapeutic interventions. Vasoactive intestinal peptide (VIP) and pituitary adenylate cyclase-activating peptide (PACAP) receptors have been evaluated in human tumors and in their tissues. The VIP/PACAP receptor subtypes VPAC1, VPAC2, and PAC1 were evaluated in these tissues by determining the rank order of potencies of VIP and PACAP as well as VPAC1- and VPAC2-selective analogues.

The VIP/PACAP receptors expressed in the great majority of the most frequently occurring human tumors, including breast (100% receptor incidence), prostate (100%), pancreas (65%), lung (58%), colon (96%), stomach (54%), liver (49%), and urinary bladder (100%) carcinomas as well as lymphomas (58%) and meningiomas (100%), are predominantly of the VPAC1 type. the high VIP/PACAP receptor expression in tumors may represent the molecular basis for clinical applications of VIP/PACAP such as in vivo scintigraphy and radiotherapy of tumors as well as VIP/PACAP analogue treatment for tumor growth inhibition.

Vasoactive intestinal peptide receptor-based imaging and treatment of tumors (Review)

This publication showed that VIP receptors are very important in the biology of many malignancies and are overexpressed in many tumors; thus, VIP receptors can be targeted by receptor-specific molecules. The generation of radiolabeled peptides has opened new avenues for the molecular imaging and therapy of tumors. They are becoming ideal candidates for molecular imaging techniques and therapeutic interventions.

 Vasoactive intestinal peptide receptor-based imaging and treatment of tumors (Review)

1Department of Gastroenterology, Xinqiao Hospital, Third Military Medical University, Chongqing 400037; 2Department of Nuclear Medicine,

Referenced: Thakur ML, Marcus CS, Saeed S, Pallela V, Minami C, Diggles L, Le Pham H, Ahdoot R and Kalinowski EA: 99mTclabeled vasoactive intestinal peptide analog for rapid localization of tumors in humans

Thakur ML, Chakder S and Rattan S: 99mTc-labeled vasoactive intestinal peptide receptor agonist: functional studies.

Thakur ML, Marcus CS, Saeed S, Pallela V, Minami C, Diggles L, Pham HL, Ahdoot R, Kalinowski EA and Moody T: Imaging tumors in human

Vasoactive Intestinal Peptide and Pituitary Adenylate Cyclase Activating Peptide Receptor 1 (VPAC1) Targeted Detection of Genitourinary Cancer: A Urinary Assay

Prostate cancer (CaP) and bladder urothelial cancer (BUC) are the two most common malignancies in urology, and both overexpress VPAC1. VPAC1 is overexpressed at the onset of the malignancy, prior to elevation of PSA, or alteration of cell morphology. We hypothesize that VPAC1 expressed in high density on PC and BUC can be targeted for detection of shed tumor cells (STC) in voided urine, using TP4303, a VPAC1 specific biomolecule labeled with a near infrared fluorophore.

The method is simple, noninvasive, rapid and appears to detect STC in patients with known prostate and bladder malignancy with high sensitivity. VPAC1 is a promising and novel approach for accurate and non-invasive detection of CaP and BUC from voided urine.

Investigation into a novel, but simple, non-invasive approach for detection of genitourinary cancer.

Cancer remains one of the most formidable diseases of mankind. Genitourinary cancers, such as those involving prostate (CaP) and bladder urothelium, are common malignancies. However, their noninvasive diagnosis remains challenging.

Our investigation pertains to the use of voided urine, in which we selectively identify shed cancerous cells (SCC) by targeting a specific genomic biomarker to distinguish them from normal epithelial cells optically.

Genomic approach to PET imaging of prostate cancer: from mouse to man.

The need is compelling for early and accurate diagnosis of prostate cancer (PC), non-invasively. The goal is to PET image PC using 64Cu-TP3805, specific for VPAC1 receptors, expressed in high density on PC cells, but not on normal cells. 64Cu-TP3805 has (i) high affinity for VPAC1 (Kd = 3.1×10-9M), (ii) excellent stability in-vivo, and (iii) ability to image spontaneously grown PC in transgenic (TRAMP) mice that mimic pathophysiology of human PC.