Albumin-linked prostate-specific antigen-activated thapsigargin- and niclosamide-based molecular grenades targeting the microenvironment in metastatic castration-resistant prostate cancer

Abstract

Localized prostate cancer is curable via annihilation of the entire cancer neighborhood by surgery or local radiation. Unfortunately, once metastatic, no available therapy is curative. The vast majority will die despite aggressive systemic combinational androgen-ablation therapies. Thus, there is an urgent need for effective systemic therapeutics that sterilize the entire microenvironment in metastatic castration-resistant prostate cancer (mCRPC). To accomplish this goal, advantage can be taken of the unique biology of mCRPC cells. Like their normal cell of origin, mCRPCs retain expression of the prostate-specific differentiation protein, prostate-specific antigen (PSA), which they abundantly secrete into their extracellular fluid (ECF). This unique, and essentially universal, secretion of enzymatically active PSA into the ECF by mCRPCs creates an exploitable therapeutic index for activation of systemically delivered highly lipophilic toxins as “molecular grenades” covalently linked to cysteine-34 of human serum albumin (HSA) via a stable maleimide containing PSA cleavable peptide such that PSA-dependent hydrolysis (i.e., “detonation”) releases the grenades restrictively within the ECF of mCRPC. This approach decreases dose-limiting host toxicity while enhancing plasma half-life from minutes to days (i.e., pharmacokinetic effect) and increasing the tissue concentration of the maleimide coupled albumin delivery (MAD) in the ECF at sites of cancer due to the enhanced permeability of albumin at these sites (i.e., enhanced permeability and retention effect). This allows the MAD-PSA detonated grenades to circulate throughout the body in a non-toxic form. Only within sites of mCRPC is there a sufficiently high level of enzymatically active PSA to efficiently “pull the pin” on the grenades releasing their lipophilic cell-penetrant toxins from HSA. Thus, if a sufficient level of “detonation” occurs, this will kill mCRPC cells, and sterilize the entire PSA-rich metastatic sites via a bystander effect. In this review, two examples of such MAD-PSA detonated molecular grenades are presented—one based upon thapsigagin and the other on niclosamide.

The endoplasmic reticulum Ca2+‐ATPase SERCA2b is upregulated in activated microglia and its inhibition causes opposite effects on migration and phagocytosis

“…However, it has been reported that prolonged exposure to thapsigargin can cause stress in the ER and other Ca 2+ stores, and subsequently may evoke the unfolded protein response, caspase activation, mitochondrial release of apoptotic factors, and activation of Ca 2+ ‐dependent endonucleases, eventually resulting in cell death (Foufelle & Fromenty, 2016; Tabas & Ron, 2011). In fact, local SERCA2b inhibition by thapsigargin‐derivates and its effect on Ca 2+ signaling has been recently explored as a potential anti‐cancer therapy (Akinboye, Brennen, Denmeade, & Isaacs, 2019; Doan et al, 2015; Mahalingam et al, 2016). Although SERCA2b is ubiquitously expressed, this strategy relies on local activation of an inactive thapsigargin prodrug in the tumor environment, which may cause death specifically in the cancer cells.…”

Large Scale Conversion of Trilobolide into the Payload of Mipsagargin: 8-O-(12-Aminododecanoyl)-8-O-Debutanoylthapsigargin

“…Despite the polar peptide, mipsagargin most likely penetrates cell membranes, causing systemic toxicity in patients [21]. However, a novel and more complex strategy for specific Tg targeting has been introduced and evaluated for possible treatment of metastatic castration-resistant prostate carcinoma [22,23]. This method is based on the coupling of PSA-targeted Tg prodrug via a 2-fluoro-5-maleimidobenzamide linker to human serum albumin (HSA) [23].…”

“…However, a novel and more complex strategy for specific Tg targeting has been introduced and evaluated for possible treatment of metastatic castration-resistant prostate carcinoma [22,23]. This method is based on the coupling of PSA-targeted Tg prodrug via a 2-fluoro-5-maleimidobenzamide linker to human serum albumin (HSA) [23]. Coupling to HSA offers favorable properties for the prodrug, such as long half-life in blood, prevention of nonselective permeation into benign cells [1,23], and accumulation in cancer tissue.…”

“…This method is based on the coupling of PSA-targeted Tg prodrug via a 2-fluoro-5-maleimidobenzamide linker to human serum albumin (HSA) [23]. Coupling to HSA offers favorable properties for the prodrug, such as long half-life in blood, prevention of nonselective permeation into benign cells [1,23], and accumulation in cancer tissue.…”

In honor of Dr. Donald S. Coffey – Prostate cancer biology and therapy

“…The development of novel agents targeting non-AR mechanisms holds great promise to treat PCa that does not respond to AR-targeted therapies. Finally, Dr. John T. Isaacs and colleagues [11] described novel systemic therapeutics that sterilize the entire microenvironment in metastatic CRPC (mCRPC). This novel approach is based on albumin-linked prostate-specific antigen (PSA)-activated thapsigargin- and niclosamide-based molecular grenades targeting the microenvironment in mCRPC.…”