Introduction

Acid phosphatase (AP) is an enzyme that catalyzes the hydrolysis of phosphate esters in an acidic environment. This chemical reaction is essential to different metabolic processes. Therefore, AP exists in several biological kingdoms, including plants, animals, fungi, and even bacteria. Research has shown AP to play a pivotal role in different physiological processes in humans, including bone resorption, immune defenses, pathogen clearance, epithelial growth regulation, and iron transport, among others.[1]

Pathophysiology

The acid phosphatase family generally divides into two major groups depending on the presence or absence of a binuclear metal center. The first group (metallohydrolases) shows a characteristic purple color due to charge transfer from tyrosine residue to Fe(III), thus called purple acid phosphatases (PAP). They also can be differentiated from the other group of acid phosphatases by their insensitivity to tartrate inhibition, so they were called tartrate-resistant acid phosphatases (TRAP).[1][2]

Clinical Significance

As Marker: Acid phosphatase can be detected normally in blood at a level of ≤ 2 ng/mL. Due to its secretion from different tissues, it is a non-specific marker and is, therefore, more valuable in monitoring response to therapy and prognosis than diagnosis. Prostate cancer is one of the most common cancers in men worldwide. A specific form of AP, sensitive to tartrate inhibition, called secretory prostatic acid phosphatase, is normally secreted by prostate tissue. However, cancerous prostate tissue tends to overexpress it. In fact, 95% of patients with prostate cancer have high levels of AP, especially if metastasized to bones. Therefore, it was the major serum marker for prostate cancer used in screening and staging but has recently been replaced with a more specific marker, the prostate-specific antigen (PSA). Nonetheless, prostatic acid phosphatase measurement is still being used in forensic cases as it is actively released in seminal fluid and can be used to identify seminal fluid in law enforcement cases.[3]

Bone tissue is a dynamic tissue that is continuously being formed and resorbed in a balanced fashion. Osteoclasts, the cells responsible for bone resorption, express another isoform of acid phosphatase. Indeed, several studies have shown that acid phosphatase is directly involved in bone resorption. Bone AP differs from prostatic AP in being a tartrate-resistant acid phosphatase (TRAP). In osteoporosis, the most common bone disease in humans, the resorption/formation balance becomes disrupted in favor of resorption. Several serum markers for bone resorption have been proposed, such as urinary hydroxyproline, total urinary pyridinoline, and bone sialoprotein. TRAP was found to be precise, resistant to hemolysis, and has minimal day to day variability. Therefore, it has been suggested to monitor response to therapy, but still under development. Also, agents that inhibit TRAP, such as fluoride, have been shown to improve and even reverse osteoporosis cases.[4][5]

Acid phosphatase has also undergone evaluation in malignancies. In hairy cell leukemia (HCL), a chronic lymphoproliferative disease in which neoplastic B cells infiltrate the bone marrow, spleen, and blood, leading to splenomegaly, anemia, and recurring infections. Leukemic cells in HCL have an intracytoplasmic TRAP enzyme. In most patients, aspirates from blood or bone marrow are testable for the presence of TRAP, which showed to be quite sensitive and specific to HCL, hence aid in detection and diagnosis.[6] Furthermore, when metastasizing to bones, several types of malignancies can induce bone resorption through several steps, including higher expression of AP. It thus can be used as a serological and histological prognostic marker as well as to monitor response to treatment.[7][8] Another clinical entity where AP can be useful is Gaucher disease (GD), the most common lysosomal storage disease seen worldwide. GD commonly presents with unexplained hepatosplenomegaly and pancytopenia. It is treatable by a continuous replacement of the deficient enzyme, glucocerebrosidase. A serum maker called “chitotriosidase” is usually used to monitor the disease burden and response to enzyme replacement. However, when it is normal, TRAP may be used instead as a marker.[9]

As Therapeutic Target: As noted above, AP as a marker has largely been replaced by more sensitive and specific markers; however, it gained more interest as a target for immunotherapy against cancers in the past decade. A novel strategy to eliminate cancer cells is through cancer vaccines that stimulate the adaptive immune system (similar to any other vaccine) to target cells with certain antigens expressed on cancerous cells. These antigens can be tumor-specific, exclusively expressed on cancerous cells, or non-specific antigens expressed on both normal cells and cancerous cells; however, they are much higher expressed on cancerous cells, such as prostatic acid phosphatase.[10] 

Sipuleucel-T is an immunological agent composed of fusion protein combining prostatic AP with granulocyte-macrophage colony-stimulating factor. The process involves the extraction of the patient’s autologous dendritic cells by leukapheresis, which then are loaded with Sipuleucel-T ex vivo and then re-infused to the patient. The dendritic cells will stimulate T-cells to target cells expressing prostatic AP. Three pivotal phase-3 placebo-controlled clinical trials showed that administration of sipuleucel-T every two weeks for a total of 3 doses in patients with androgen-independent prostate cancer increased the median survival by greater than or equal to four months (p=0.01) when compared to placebo. Therefore, it has been approved by the FDA for hormone-refractory metastatic prostate cancer.[11] Moreover, several clinical trials are underway to assess sipuleucel-T efficacy in earlier stages of prostate cancer as well as its efficacy when combined with different other chemotherapeutic agents. Other immunotherapeutic strategies targeting prostatic acid phosphatase are also being developed, such as using plasmid DNA vaccines encoding prostatic AP. Carriers then transport these DNA vaccines to their destination in vivo, the antigen-presenting cells, which can induce an immune response. Johnson and coinvestigators developed a DNA vaccine for AP and used attenuated Listeria monocytogenes, which selectively infect antigen-presenting cells, as carriers. Two phase-I clinical trials and preclinical studies on rodent models have shown promising results, and a randomized placebo-controlled phase II clinical trial is being currently being conducting to evaluate this vaccine.[12]

Enhancing Healthcare Team Outcomes

Treatment with Sipuleucel-T requires a multidisciplinary team consisting of an oncologist, pharmacist, infusion room nurses, and a clinic nurse to coordinate the treatment. The process starts by collecting the patient’s blood using leukapheresis. The blood sample then goes to the manufacturing facility where the harvested antigen-presenting cells (APCs) are incubated with recombinant prostatic acid phosphatase and GM-CSF leading to activations of APCs. The activated APCs are then packed and returned to the infusion center, where they are infused into the patient. The approved treatment regimen involves biweekly infusions. Treatment with sipuleucel-T for one month can approximate a 100K$, making it one of the most expensive cancer treatments in the market. Although Sipuleucel-T has shown superior efficacy to docetaxel, the cost difference may barely compensate for the added median life; therefore, funding will become an obstacle. Fortunately, the Centers for Medicare and Medicaid (CMS) cover sipuleucel-T treatments. Nonetheless, involving financial personnel and social workers in the process may facilitate the funding process. Also, exploring equally effective yet less expensive options is certainly warranted to decrease the economic burden on society.[11][13]