Theranostics is a combination of the terms therapeutics and diagnostics. In this emerging field of medicine, one radioactive drug, used to diagnose, is combined simultaneously or sequentially with a second radioactive drug to deliver therapy to treat the primary tumor and any metastatic lesions.

The Future of Cancer Detection and Therapy
Despite technological advancements in the healthcare industry, cancer remains a major health threat. Although cancer screenings have become a controversial topic, the importance of early diagnosis is undisputed [1][2]. Nevertheless, there is a critical need to further develop diagnostic imaging techniques that can distinguish which tumors pose a threat, and which do not.

NV-VPAC1 Theranostics technology shows specifically where the cancer is located and follows with targeted therapy.

Prostate cancer
Prostate cancer is the third most commonly diagnosed cancer in the United States (US), surpassed only by breast and lung cancer [17]. Prostate cancer is the second leading cause of cancer deaths in men, surpassed only by lung cancer [17]. According to the American Cancer Society, in 2020, approximately 191,930 men in the US will be diagnosed with prostate cancer and an estimated 33,330 men will die from the disease. Prospective screening for prostate cancer is most often carried out with the prostate-specific antigen (PSA) test. Approximately 33 million PSA tests are conducted annually to measure the level of PSA produced by cells of the prostate gland.

In the US, the widely used cut-off value of PSA >4.0 ng/mL indicates a positive screening result, detected in 4.5 million men aged 40-69 years [18]. Since PSA is not prostate-cancer specific, it has a low specificity and elevated PSA levels also can be detected in men with benign prostatic hyperplasia (BPH) and prostatitis. PSA screening, especially when linked to a single cut-off, is therefore prone to false positives. The false-positive tests often lead to additional medical visits, the performance of unnecessary biopsies, and associated adverse effects including hematuria, rectal bleeding, hematospermia, pain, lower urinary tract symptoms, and urinary retention [19]. Persistently elevated PSA levels often lead to repeated biopsies which can be associated with significant morbidity, including infection, sepsis, bleeding, and hospitalization.

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Because the relative risks and benefits of prostate cancer screening using PSA as a diagnostic test are controversial [20][21], there is a clear and critical need to develop additional biomarkers that can improve diagnosis.

Some progress has been made, with several alternatives proposed, including the prostate health index (PHI), kallikrein panel (4K score), PCA3 gene, mRNA-based testing, TMPRSS2:ERG fusion gene, and various exosomal biomarkers [22].

Breast cancer
In 2020, it is estimated that there will be 279,100 new cases of breast cancer and 42,170 breast cancer deaths among women in the US. [16]. In the US male population, although rare, there will be approximately 2,620 new breast cancer cases and 520 breast cancer deaths in 2020 [16].

Neither self-examination nor mammography can always distinguish between masses that are malignant and those that are benign. This inability compels physicians to perform invasive procedures–such as biopsies–on patients to obtain tissue samples for histology. This process remains the gold standard for the determination of malignancy. Among the estimated 7 million breast biopsy procedures performed annually on women in the US, nearly 80% find benign pathology [5].

It has been estimated that among US women aged 50 years who have been screened annually for a decade, 3 to 14 out of 1000 will be overdiagnosed and treated needlessly. On the other hand, only 1 to 3 will avoid a breast cancer death [6]. Invasive biopsy procedures are associated with enormous health care costs, emotional trauma to patients, risks of spreading cancer, and cosmetic concerns.

Approximately 40 million mammograms are conducted annually in the US. It is estimated that 1.7 million of those mammograms result in biopsies of suspicious lesions. Of those 1.7 million biopsies, approximately 1.3 million, or 80%, resulting in a benign diagnosis. The estimated cost of those negative biopsies is nearly $4 billion.

NV-VPAC1-Cu-64 PET scan technology can significantly reduce the number of negative biopsies, improve the immediacy of a breast cancer confirmation, and decrease the false positive rate.

Biopsies and tissue histology unequivocally determine malignancy. Unfortunately, this procedure is largely based upon morphologic modulations that the cancerous cells undergo. There are characteristic biometric authentications that occur prematurely in the malignant cells that can also point to signs of cancer, including:

  • Excess hormone production
  • Receptors or proteins found on the cell surface
  • Oncogenes produced within the nucleus of the cell

These signs are silent, candid evidence of tumor growth that often go undetected because of their immaturity in comparison to the histology testing. Targeting specifically the overexpression of VPAC1 receptors accurately and efficiently with the NV-VPAC1-Cu-64 and NV-VPAC1-Cu-67 Theranostic application is a practical and scientifically valid approach for early diagnosis and treatment of various tumors and is especially relevant for prostate and breast cancers.

Current imaging techniques are inadequate, missing up to 30% of cancers [7]. Furthermore, current imaging methods cannot distinguish benign from malignant tumors [7]. Thus, more sensitive imaging methods are needed. NV-VPAC1-Cu-64 PET imaging, which provides VPAC1 receptor-specific tumor imaging, may be advantageous since it can demonstrate the state of malignancy and clearly distinguish between benign and malignant tumors.

The NV-VPAC1 Theranostic Approach Allows for Confirmatory Testing
VPAC1 receptors are named for the combined vasoactive intestinal peptide (VIP) plus the pituitary adenylate cyclase-activating peptide (PACAP) family of cell surface receptors.

The VPAC1 receptor is classified as a Type II binding site of the PACAP receptor family [8,9]. The human VPAC1 receptor gene encodes a G protein-coupled receptor that recognizes both VIP- and PACAP-related peptides with high affinity [8,9]. VPAC1 receptors are overexpressed in numerous cancers, including prostate, breast, colon, liver, lung, pancreatic, bladder, thyroid, and uterine cancer [10]. The overexpression of VPAC1 receptors occurs on the surface of malignant cells and precedes histologic changes [11] [12]. Prostate and breast cancer cells are said to express approximately 104 receptors per cell [11][13][14]. VIP and PACAP have been shown to activate adenylate cyclase, increase VEGF (vascular endothelial growth factor) expression and secretion, and stimulate growth in various breast cancer cell lines [10].

VPAC1-specific peptides were designed and synthesized by Dr. Mathew Thakur and colleagues at Thomas Jefferson University (TJU), Philadelphia, PA. Their hypothesis suggests that radiolabeled biomolecules with a high affinity for VPAC1 receptors could be used in vivo to image cancer cells. This breakthrough technology aids in both the early detection and localization of cancer cells. On the basis of their high affinity for VPAC1 receptors, Cu-64, a positron-emitting isotope, (half-life [t½]=12.7 hours), and Copper-67 (Cu-67), a beta-emitting isotope, (half-life [t½]=61.8 hours or 2.7 days), were more sensitive than other imaging modalities, identifying all malignant tumors that overexpressed VPAC1, and did not identify benign tumors that did not overexpress VPAC1 receptors.

NV-VPAC1-Cu-64 works effectively for prostate and breast cancer diagnosis as a companion diagnostic scan following an annual exam or screening mammogram. The NV-VPAC1-Cu-64 PET scan targets VPAC1 receptors, which are overexpressed on the surface of malignant cells, early in the onset of prostate and breast cancers. This confirmatory test allows physicians to quickly determine whether the patient has cancer. In addition, NV-VPAC1-Cu-67 PET ensures targeted therapy for treating patients with cancer.

The combined NV-VPAC1™ Theranostics application reduces the number of unnecessary future screenings and mammograms; minimizes patient anxiety, fear, and depression; and greatly decreases health care costs.

References
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[2] Euhus D, Di Carlo PA, Khouri NF. Breast Cancer Screening. Surg Clin North Am. 2015 Oct;95(5):991-1011.
[3] Hubbard RA, Kerlikowske K, Flowers CI, Yankaskas BC, Zhu W, Miglioretti DL. Cumulative probability of false-positive recall or biopsy recommendation after 10 years of screening mammography: a cohort study. Ann Intern Med. 2011 Oct 18;155(8):481-92.
[4] Braithwaite D, Zhu W, Hubbard RA, O’Meara ES, Miglioretti DL, Geller B, et al. Screening outcomes in older US women undergoing multiple mammograms in community practice: does interval, age, or comorbidity score affect tumor characteristics or false positive rates? J Natl Cancer Inst. 2013 Mar 6;105(5):334-41.
[5] Elter M, Schulz-Wendtland R, Wittenberg T. The prediction of breast cancer biopsy outcomes using two CAD approaches that both emphasize an intelligible decision process. Med Phys. 2007 Nov;34(11):4164-72.
[6] Welch HG, Passow HJ. Quantifying the benefits and harms of screening mammography. JAMA Intern Med. 2014 Mar;174(3):448-54.
[7] Thakur ML, Devadhas D, Zhang K, Pestell RG, Wang C, McCue P, et al. Imaging spontaneous MMTVneu transgenic murine mammary tumors: targeting metabolic activity versus genetic products. J Nucl Med. 2010 Jan;51(1):106-11.
[8] Gottschall PE, Tatsuno I, Miyata A, Arimura A. Characterization and distribution of binding sites for the hypothalamic peptide, pituitary adenylate cyclase-activating polypeptide. Endocrinology. 1990 Jul;127(1):272-7.
[9] Lam HC, Takahashi K, Ghatei MA, Kanse SM, Polak JM, Bloom SR. Binding sites of a novel neuropeptide pituitary-adenylate-cyclase-activating polypeptide in the rat brain and lung. Eur J Biochem. 1990 Nov 13;193(3):725-9.
[10] Moody TW, Nuche-Berenguer B, Jensen RT. Vasoactive intestinal peptide/pituitary adenylate cyclase activating polypeptide, and their receptors and cancer. Curr Opin Endocrinol Diabetes Obes. 2016 Feb;23(1):38-47.
[11] Trabulsi EJ, Tripathi SK, Gomella L, Solomides C, Wickstrom E, Thakur ML. Development of a voided urine assay for detecting prostate cancer non-invasively: a pilot study. BJU Int. 2017 Jun;119(6):885-95.
[12] Moody TW, Gozes I. Vasoactive intestinal peptide receptors: a molecular target in breast and lung cancer. Curr Pharm Des. 2007;13(11):1099-104.
[13] Lelievre V, Pineau N, Waschek J. The biological significance of PACAP and PACAP receptors in human tumors from cell lines to cancer. In Endocrine Updates: Vaudry H, Arimura A, eds, Springer-Verlag, New York, NY. 2003;Volume 20:361-99.
[14] Leyton J, Gozes Y, Pisegna J, Coy D, Purdom S, Casibang M, et al. PACAP(6-38) is a PACAP receptor antagonist for breast cancer cells. Breast Cancer Res Treat. 1999 Jul;56(2):177-86.
[15] Thakur ML, Aruva MR, Gariepy J, Acton P, Rattan S, Prasad S, et al. PET imaging of oncogene overexpression using 64Cu-vasoactive intestinal peptide (VIP) analog: comparison with 99mTc-VIP analog. J Nucl Med. 2004 Aug;45(8):1381-9.
[16] American Cancer Society. Cancer Facts and Figures 2020. Atlanta, GA: American Cancer Society, 2020.
[17] National Cancer Institute Surveillance, Epidemiology, and End Results Program. Cancer Stat Facts: Prostate Cancer. 2017 [Accessed October 14, 2017]; Online. Last accessed on December 29, 2020 .
[18] Lin K, Lipsitz R, Janakiraman S. Benefits and Harms of Prostate-Specific Antigen Screening for Prostate Cancer: An Evidence Update for the U.S. Preventive Services Task Force [Internet]. 2008 Aug Evidence Update for the U.S. Preventive Services Task Force.
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[20] Chou R, Croswell JM, Dana T, Bougatsos C, Blazina I, Fu R, et al. Screening for prostate cancer: a review of the evidence for the U.S. Preventive Services Task Force. Ann Intern Med. 2011 Dec 06;155(11):762-71.
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[22] Filella X, Foj L. Prostate Cancer Detection and Prognosis: From Prostate Specific Antigen(PSA) to Exosomal Biomarkers. Int J Mol Sci. 2016 Oct 26;17(11).

Featured image © 2020 NuView Life Sciences/Zentralklinik Bad Berka.

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