Cancer Metastasis Rev DOI 10.1007/s10555-014-9530-4

NON-THEMATIC REVIEW

New approaches to selectively target cancer-associated matrix metalloproteinase activity Marilena Tauro & Jeremy McGuire & Conor C. Lynch

# Springer Science+Business Media New York 2014

Abstract Heightened matrix metalloproteinase (MMP) activity has been noted in the context of the tumor microenvironment for many years, and causal roles for MMPs have been defined across the spectrum of cancer progression. This is primarily due to the ability of the MMPs to process extracellular matrix (ECM) components and to regulate the bioavailability/activity of a large repertoire of cytokines and growth factors. These characteristics made MMPs an attractive target for therapeutic intervention but notably clinical trials performed in the 1990s did not fulfill the promise of preclinical studies. The reason for the failure of early MMP inhibitor (MMPI) clinical trials that are multifold but arguably principal among them was the inability of early MMP-based inhibitors to selectively target individual MMPs and to distinguish between MMPs and other members of the metzincin family. In the decades that have followed the MMP inhibitor trials, innovations in chemical design, antibody-based strategies, and nanotechnologies have greatly enhanced our ability to specifically target and measure the activity of MMPs. These advances provide us with the opportunity to generate new lines of highly selective MMPIs that will not only extend the overall survival of cancer patients, but will also afford us the ability to utilize heightened MMP activity in the tumor microenvironment as a means by which to deliver MMPIs or MMP activatable prodrugs.

Keywords Matrix metalloproteinase . Extracellular matrix . Activity-based protein probes . Tumor microenvironment . Cancer progression and metastasis

M. Tauro : J. McGuire : C. C. Lynch (*) Departments of Tumor Biology, Moffitt Cancer Center and Research Institute, 12902 Magnolia Dr., SRB-3, Tampa, FL, USA e-mail: [email protected]

1 Introduction In the human degradome, there are 569 proteinases divided into broad categories depending on their catalytic domains [1]. The metalloproteinase family is comprised of 194 intracellular, integral membrane, pericellular, and extracellular enzymes that are dependent on the presence of a metal ion in the catalytic domain to process substrates. Metalloproteinases can be further sub-categorized largely based on their structure, for example, ADAM (a disintegrin and metalloproteinase) and ADAMTS (ADAM with a thrombospondin motif) or on their substrate specificity, for example, matrix metalloproteinases (MMPs). In humans, there are 23 MMPs of which 17 are secreted and 6 are membrane bound [2]. Collectively, MMPs are capable of processing components of the extracellular matrix including the basement membrane. MMP structure typically consists of four distinct domains: the N-terminal prodomain, catalytic domain, hinge region, and a C-terminal hemopexinlike domain that contributes to macromolecular substrate recognition (Fig. 1). The membrane-type MMPs (MT-MMPs; MMP-14, 15, 16, 17, 24, and 25) have additional transmembrane domains or glycosylphosphatidylinositol (GPI) anchors that tether them to the cell surface [3]. MMP expression and activity are tightly regulated at the gene and post-translational level. They are typically generated as an inactive enzyme that requires the removal of a pro-domain by other MMPs or proteinases (Fig. 2a). To prevent excessive ECM degradation and restore tissue homeostasis, MMP activity can be mitigated by endogenously produced tissue inhibitor of metalloproteinases (TIMPs) [4]. However, in the tumor microenvironment, the delicate balance between MMP activity and inhibition is often tipped in favor of proteolysis. Metastasis is responsible for approximately 90 % of cancer deaths and treatment of metastatic disease remains a major clinical challenge. Cancer cell intravasation and extravasation

Cancer Metastasis Rev Fig. 1 MMP family and structural domains. PRCGVPD motif illustrates the cysteine switch among MMP family members. The RXKR motif allows for the activation of membrane-type MMPs by proprotein convertases. TM refers to the transmembrane domain while GPI indicates the glycosylphosphatidylinositol anchor utilized by MMP-17 and MMP-25. IgG indicates immunoglobulin-like domains on the type II transmembrane MMPs, MMP-23A and B

SIGNAL PRO-DOMAIN PEPTIDE MATRILYSINS MMP-7 MMP-26

SH

COLLAGENASES MMP-1 MMP-8 MMP-12 MMP-13 MMP-18 MMP-19 MMP-20 MMP-21

Zn++

SH

Zn++

SH

Zn++

SH

Zn++

PRCGVPD

GELATINASES MMP-2 MMP-9 STROMELYSINS MMP-3 MMP-10 MMP-11 MEMBRANE TYPE MMP-14 MMP-15 MMP-16 MMP-24

SH

GPI-ANCHORED MMP-17 MMP-25

SH

TYPE II TRANSMEMBRANE MMP-23 A MMP-23 B

CATALYTIC DOMAIN

RXKR

HINGE REGION

Zn++ Zn++ IGG

SH

N-TERMINAL SIGNAL ANCHOR

through basement membranes are essential steps in the metastatic cascade. More than 30 years ago, dysregulated MMP activity was implicated in the process of cancer metastasis giving rise to the hypothesis that MMP inhibition would prevent patient metastasis and prevent cancer-related deaths [5]. This led to the generation of peptidomimetic and non-peptidomimetic sequences that had the ability to bind to the zinc ion in the catalytic domain and prevent MMP activity [6]. Clinical trials performed in the 1990s that focused on MMP inhibition as a therapy to extend overall survival were largely unsuccessful, in some cases performing worse than placebo. The trial results and limitations have been reviewed extensively but the overall conclusion is that these inhibitors entered into the clinical setting prematurely [7, 8]. For example, at the time of the first clinical trial, three MMPs had been identified and the inhibitory effects of MMPIs on other members of the metzincin family such as the ADAMs were unknown [9]. Additionally, patients selected for some of the clinical trials already had late stage disease making the impact of the MMPIs on metastasis difficult to determine with side effects such as arthralgia and myalgia also preventing maximal dosing [10, 11]. The inability and lack of MMPI efficacy readouts in cancer tissues further obscured the results of the

Zn++

Cys

trials in that it was difficult to determine if applied MMPIs were reaching the intended tumor microenvironment. MMPs have now been demonstrated to be potent regulators of growth factor and cytokine bioactivity and bioavailability, a characteristic largely underappreciated at the time of the first clinical trial [9, 12]. Advances in proteomic technology have defined a large repertoire of non-matrix substrates for MMPs and illustrated the vast impact a single MMP can have on cell signaling and behavior [13]. These matrix and non-matrix functions do not always result in a protumor effect with studies demonstrating striking protective roles for MMPs in specific cancers such as MMP-3 and -8 in skin cancer and MMP-9, -12, and -19 being implicated in the generation of fragments that prevent angiogenesis in the tumor microenvironment [14]. Additionally, new insights have also defined that MMPs can function in a non-catalytic manner. For example, the cytosolic tail of membrane tethered MMP-14 can contribute to osteoclast fusion and maturation via regulating the activity of Rac1, while MMP-3 can control mammary epithelial invasion via the interaction between the hemopexin domain and heat shock protein-90β (HSP-90 β) [15, 16]. Collectively, the results of clinical trials and subsequent studies have demonstrated that if MMP inhibition is to be utilized as a viable strategy to treat cancer, a clear understanding of the

Cancer Metastasis Rev

A

PRO-MMP

CYSTEINE SWITCH

S1 Zn++

S1 Zn++

S1 Zn++

SO2H

H2O:

S Ex

HYDROXAMATE CARBOXYLATE

Ex

C

Ex

D

E S1 Zn++

S1 Zn++

S1 Zn++

O

R

Ex

B

ACTIVE MMP

THIOLATE

PHOSPHONATE

O N H

OH

R

OH

Ex

Ex R1 R

N

R1

R2

BISPHOSPHONATE

Fig. 2 MMP activation and chemical strategies for inhibition. a MMPs are typically secreted as a latent enzyme with the cysteine residue in the propeptide domain coordinating with the zinc ion to prevent activity. Proteolytic cleavage of the propeptide domain by other proteases leads to hydrophilic attack of the cysteine-zinc bond. Displacement of the prodomain peptide then allows for enzyme activation. The catalytic domain of MMPs is composed of several pockets (S) with the S1’ pocket

considered “the pocket of specificity.” Exosites (Ex) can also allow for specific substrate recognition. b MMP inhibitor strategies have largely revolved around chelating or coordinating the zinc ion to prevent enzymatic activity. c–e As noted, the interaction of small molecule MMPIs can result in non-specificity (c) but exosites located far from the active site can be utilized for either allosteric inhibition (d), or by inhibitors that can simultaneously interact with both the catalytic site and the exosite (e)

roles of individual MMPs in the context of specific cancers is required. Major hurdles to realizing future successful MMPI clinical trials include the development of highly specific MMP inhibitors and the ability to quantitate the efficacy of those inhibitors in the in vivo tumor microenvironment. However, recent advances in chemical design strategy combined with greater understanding of natural inhibitors; antibody-specific targeting and imaging approaches could fulfill the promise of MMP inhibition as a cancer treatment.

MMPs in tissues can be identified using mass spectroscopy. Approaches such as these are essential to defining key MMPs involved in disease progression and in turn can provide strong rationale for the selective inhibition of chosen MMPs. However, once individual MMPs have been identified, designing an inhibitor that is highly selective and spares the activities of others remains a challenge. Traditionally, MMP inhibitors were generated using structure-based drug design, a technique that has been widely employed in medicinal chemistry to target molecules of interest. The approach involves assessing the structure-activity relationship (SAR) of the enzyme/new chemical entity complex combined with high-resolution X-ray, crystallography studies, and nuclear magnetic resonance (NMR) techniques to identify highly potent and selective inhibitors. Although MMPs are structurally well defined, the presence of flexible domains within the enzyme impacts the ability to identify highly selective inhibitors. However, conserved structural characteristics such as the requirement of a zinc ion for MMP activity offer a means through which to generate MMP selective inhibitors. Historically, this was achieved by grafting zinc-binding groups (ZBGs) onto structural backbones that could dock into the active site of a specific MMP (Table 1). Early studies revealed that hydroxamates were excellent chelators of the zinc ion [18]. Specificity towards

2 Chemical strategies to target MMP catalytic activity In order to circumvent issues associated with broad-spectrum MMPIs, it is important to identify the individual MMPs that contribute to cancer progression. This can be achieved using cancer models in which a specific MMP is silenced or overexpressed in the cancer and/or host compartments. Numerous roles for MMPs have been identified in this manner. In vivo, novel approaches have also been taken to identify the activity status of individual MMPs in the cancer environment. For example, photoreactive activity-based protein probes (ABPP) have been developed to assess the activity status of MMPs in tissues [17]. By coupling a zinc-chelating hydroxamate to a benzophenone photocrosslinker, active

Cancer Metastasis Rev Table 1 Current and past human clinical trials with MMP inhibitors Drug

Chemical classification

MMP specificity

Cancer type

Trials phase

Start year

Results/Notes

Marimastat BB-2516 Hydroxamate Peptidic Prinomastat AG3340 Hydroxamate Non-peptidic

MMP-1, -2, -7, -9, and - NSCLC, breast, and 14 pancreatic cancer MMP-2, -9, -13, and -14 Glioblastoma, melanoma, breast and esophageal cancer

III

1999

III

1999/2000

Cipemastat RO323555 Ilomastat GM6001

Hydroxamate

MMP-1

Rheumatoid arthritis

III

2000

Hydroxamate

Broad spectrum

II-III

MM1270

Hydroxamate

Broad spectrum

Corneal ulceration and diabetic retinopathy Advanced cancers and brain injury

Rebimastat BMS275291 (a)

Thiol-based

Broad spectrum

NSCLC, hormone, refractory prostate cancer

III

Tanomastat BAY 12- Carboxylic 9566 acid Disulfiram Sulfonamide

MMP-2, -3, and -9

Advanced cancers

III

MMP-2 and -9

I

Recruiting

Genistein

Isoflavone

MMP-2 and -9

I

Recruiting

Ongoing

AZD1236

Sulfonamidebased Hydroxamate sulfone Doxycycline

MMP-9, and -12

Refractory solid tumors, melanoma, and glioblastoma Advanced cancers such as breast, prostate, and pancreatic cancer Chronic obstructive pulmonary disease Hepatitis C

Musculoskeletal side-effect Lack of effectiveness in patients with late-stage disease Lack of effectiveness Broad spectrum side effects Musculoskeletal side-effect and skin rashes Musculoskeletal pain and inflammation Lack of effectiveness Ongoing

II

2008

Ongoing

III

2007/2009

Ongoing

1998

In clinical use

1999

Disease stabilization but not response Lack of effectiveness

CTS1027 Periostat Metastat COL-3

Neovastat AE941

Broad spectrum no MMP-1 Broad spectrum

Chemically MMP-2 and -9 modified tetracycline Shark cartilage MMP-2, -9, and -12 extract

I

Periodontitis and chronic approved wound Kaposi’s sarcoma and II refractory metastatic cancer Renal cells carcinoma, multiple myeloma, and breast/colorectal cancer

III

2000/2002

2000/2001

All data obtained from clinicaltrials.gov or National Cancer Institute of Canada-Clinical Trials data (a)

individual MMPs would subsequently be achieved by utilizing the depth of the S1 and S1’ sub-pockets surrounding the active site. These approaches using peptidomimetic and nonpeptidomimetic backbones formed the bulk of the hydroxamate MMP inhibitors that went into clinical trials but were ultimately unsuccessful due to their broad range activity; dose limiting side effects; in vivo instability; and low oral availability [19–22]. To address the limitations of the hydroxamates, alternative ZBGs that coordinate rather than completely chelate the zinc ion have been utilized including sulfhydryl, phosphonic, and carboxyl groups (Fig. 2b). Coordination rather than chelation may allow for more flexibility in regards to the designing more selective inhibitors. As an example, by exploiting subpocket characteristics, SB-3CT was identified as a potent inhibitor of the gelatinases, MMP-2, and MMP-9. The SB-

3CT mechanism of action involves the direct binding to the zinc ion in the catalytic site, followed by an enzyme-catalyzed ring-opening of the thiirane resulting in a zinc-thiolate complex [23]. X-ray absorption spectroscopy technique confirmed a direct coordination of the zinc by the sulfur atom of the bound inhibitor [24]. This interaction results in a conformational reconstruction around the active site returning the enzyme in the pro-active structure. SB-3CT has been used in preclinical models of T-cell lymphoma [25] and prostate cancer metastasis to bone [26]. Of note, carbamate derivatives of SB-3CT that are highly selective for MMP-2 can cross the blood–brain barrier and, therefore, have potentially important treatment implications for brain metastases [27]. Other groups that can be successfully utilized as ZBGs include acetohydroxamic acid (AHA) for the synthesis of heterocyclic ZBGs, hydroxypyridinones, pyrones, hydroxypyridinethiones, and

Cancer Metastasis Rev

thiopyrones, each group providing varying degrees of coordination hence inhibition [28]. In addition to targeting cancers using the systemic delivery of ZBG inhibitors, the selective targeting of certain organs or tissues is also plausible. Bone metastases and skeletal malignancies such as multiple myeloma can cause extensive bone damage and the resultant lesions greatly impact the patient’s quality of life. Bisphosphonates have been used clinically to treat cancer-induced bone disease for several years. They target the skeleton due to their affinity for hydroxyapatite. Studies have shown that the primary mechanism of bisphosphonate action is the apoptosis of bone resorbing osteoclasts. Interestingly, bisphosphonates have also been shown to downregulate MMP expression and directly inhibit their activity [29]. Roles for individual MMPs in context of skeletal malignancy have been described. For example, MMP-2 derived from the cancer cell and host compartment has been shown to contribute to the progression of bone metastases [30]. Given that bisphosphonates are highly tolerated in the clinical setting, their chemical modification to improve the impact on MMP inhibition represents an exciting dual approach for the treatment of cancer-associated bone disease. Innovative approaches have led to the development of compounds comprised of a bisphosphonic moiety and selective MMP inhibition towards MMP-2 (Fig. 3). Given the noted musculoskeletal side effects in MMPI clinical trials, the utilization of boneseeking MMP inhibitors may be counter-intuitive. However, the MMPI impact on musculoskeletal system was largely joint rather than bone related, and potentially due to an inability to solubilize tumor necrosis factor (TNF) [11]. Therefore, the use of bone seeking MMP inhibitors that target sites of cancer-

induced bone turnover could eliminate deleterious side effects of systemically delivered MMPIs. Chemistry strategies such as “click-chemistry” also offer the opportunity to generate highly specific MMP inhibitors [32]. The underlying principal of the approach is that the target protein catalyzes the conjugation of two small molecules to create highly selective ligands that in turn can bind to the target protein with antibody-like affinity. The straightforward reactions are characterized by high yields, purity, and regiospecificity. Click chemistry can be used for the design of MMP inhibitors via the in situ assembly of inhibitors inside MMP binding pocket. Similar approaches have been successfully employed for other enzymes such as acetylcholinesterase (AChE) [33]. AChE acted as the reaction bait and selected possible pairs of reactants in the synthesis of its own highly regioselective inhibitor, by an equilibrium-controlled sampling of various combinations until the irreversible cycloaddition (azidealkyne cycloaddition) between azide and acetylene essentially “froze” the pair that best fit into AChE’s fits binding pocket. Using a similar strategy, molecule-based MMP inhibitors that target MMPs such as MMP-7 and -13 have been generated [34, 35]. These selective probes can target individual MMPs but a major advantage lies in the ability to link putative inhibitors to imaging molecules such as rhodamine in order to generate diagnostic molecules that provide readouts as to the localization of the MMPI and MMP activity by proxy. An area that remains relatively underdeveloped in regards to the generation of small molecule MMP inhibitors is the exploitation of the catalytic domain subsites that can provide better specificity and inhibition constants. The majority of

C BMMPI

A

B

TGF-

MMP-2

Fig. 3 Targeting the tumor-bone microenvironment with bone seeking selective MMP inhibitors [31]. a The bisphosphonic moiety allows for the binding of MMP-2 selective MMP inhibitors (BMMPIs) to calcium within bone matrix. b Osteoclast-mediated bone resorption in areas of skeletal malignancy causes osteoclast apoptosis (due to the bisphosphonate action) and the solubilization of the BMMPI inhibitor in the local

cancer-bone microenvironment. c MMP-2 derived from cancer cells and osteoblasts has previously been shown to mediate cancer survival and growth in part by regulating the bioavailability of TGFβ. Selective inhibition of MMP-2 with BMMPIs would therefore not only limit the extent of bone resorption but also starve the cancer of nutrients required for growth

Cancer Metastasis Rev

MMPIs have relied on designs that focus on the S1’ subsite. However, even the far and unprimed subsites should be taken into consideration in the future design of highly selective MMP inhibitors that will be effective for the treatment of cancer (Fig. 2c).

3 Harnessing natural MMP inhibitors for clinical use For decades, plants, fungi, and marine life have served as an important starting point for drug design and have yielded powerful chemotherapies such as taxol/paclitaxel [36]. Similarly, bacteria have yielded a number of antibiotics such as tetracyclines that additionally act as potent suppressors of MMP expression and activity. In fact, a chemically modified derivative of tetracycline, doxycycline hyclate (Periostat) is currently the only FDA approved MMP inhibitor for the treatment of periodontal disease [37]. Other modified tetracyclines such as CMT-3/COL-3/Metastat have been used in clinical trials for patients with diverse cancers but the results of these trials have been inconclusive with a number indicating that further exploration not warranted (Table 1) [38]. However, CMT-3 does appear to have good indications for the treatment of AIDS-associated Kaposi’s sarcoma [38, 39]. Crude and refined extracts derived from plants and fungi also have excellent activity against MMPs (Table 2). For the most part, polyphenols in the extracts are responsible for the observed inhibition of MMP expression and activity. Polyphenol rich diets are strongly linked with health benefits due to their antioxidant properties and their ability to suppress mitogen signaling. Polyphenols encompass over 8000 molecules of which half are flavones [63]. In addition to antioxidant properties, flavones and isoflavones have been implicated in downregulating MMP expression. For example, genistein, isolated from soybeans, has been shown to inhibit the expression of MMP-1, -9, -14, -15, and -16 while nobiletin derived from the peels of citrus fruits can downregulate the expression of MMP-1, -2, -7, and -9. Perhaps the most wellknown MMP inhibitors derived from natural polyphenol products are the catechins that can both suppress MMP expression and their activity. Green tea is a major source of catechins such as (−)-epicatechin (EC), (−)-epicatechin-3-gallate (ECG), (−)-epigallocatechin (EGC), and (−)-epigallocatechin-3-gallate (EGCG). ECG and EGCG have been found to dose-dependently inhibit the gelatinolytic activity of MMP-2 and -9 and the elastinolytic activity of MMP-12 [64–66]. Further, EGCG is a potent MMP-14 inhibitor and can impact MMP-14-mediated collagenolysis, hence cellular invasion and MMP-2 activation [50]. The question remains as to how these existing polyphenols can be improved upon in regards to their overall inhibition profile or structurally modified in order to improve their MMP specificity. SAR analysis reveals that the galloyl groups of catechins are responsible for the MMP

inhibitory activity. Fragment-based lead design (FBLD) strategies can be utilized to improve the metal binding capacity of catechols where structural changes to the phenyl ring could create specificity in modulating the interaction with each enzymatic isoform by longer and more flexible molecules, aimed to reach the S1’ MMP specificity pocket. Natural non-polyphenol compounds can also impact the activity of MMPs. For example, ageladine A, a fluorescent alkaloid isolated from marine sponges, is capable of inhibiting MMP-1, -2, -8, -9, -12, and -13. Surprisingly, ageladine A does not have a chelating Zn2+ chemical structure suggesting an unorthodox mechanism of MMP inhibition that could be exploited for the generation of new selective MMP inhibitors [67, 68]. Perhaps, the most well-known natural nonpolyphenol MMP inhibitor to reach clinical trial stages Neovastat was derived from shark cartilage. Neovastat was shown to have antiangiogenic and antimetastatic effects in multiple studies [69]. It preferentially inhibits MMP-2 with lower Ki values for MMP-1, -7, -9, and -13 noted. The absence of dose-dependent side effects of Neovastat made the compound an ideal candidate for MMP inhibition in cancer treatment, and several phase II and III clinical trials with nonsmall cell lung cancer, refractory multiple myeloma, metastatic kidney cancer, and advanced colorectal or breast cancer were performed. However, trial results in NSCLC, breast, and colorectal cancer have indicated that Neovastat does not significantly improve the outcomes while the outcomes of other trials yet to be reported [70, 71]. Despite these results, the interest for natural molecules as sources of drug lead compounds against MMPs and others continues to be high although they tend to impact multiple molecular pathways and mechanisms. However, starting from promising data on MMP inhibitory activity, medicinal chemists can develop new classes of molecules derived from natural-compounds using structure-activity relationship methodologies.

4 Using antibodies to selectively target MMPs Monoclonal antibody approaches have had great successes in cancer treatment [72]. The Her2/Neu targeted monoclonal antibody Herceptin/Trastuzumab has redefined how we treat breast cancer with additional EGF receptor targeted antibodies such as cetuximab and panitumumab also being effective treatments. Other antibody-based therapies have also proven efficacious in targeting the tumor microenvironment. For example, Ipilimumab, a monoclonal antibody that targets the cytotoxic T-lymphocyte antigen-4 (CTLA4) and prevents its inhibitory effect on cytotoxic T-lymphocytes has been shown to successfully treat patients with melanoma [73]. Bevacizumab, an antibody that targets vascular endothelial growth factor (VEGF) and prevents angiogenesis, has been

Cancer Metastasis Rev Table 2 MMP inhibitors derived from natural products Polyphenols

Name

Source

Action

Flavones

Anthraquinones

Microsporum sp.

MMP-2 (E) [40] MMP-9 (E) [40]

Nobiletin

Citrus fruit

Isoflavones

Genistein

Soy bean

Flavanoid

Silymarin

MMP-1 (E) [41] MMP-2 (E) [42] MMP-7 (E) [43] MMP-9 (E) [42, 44] MMP-1 (E) [45, 46] MMP-9 (E) [45, 46] MMP-14 (E) [45, 46] MMP-15 (E) [45, 46] MMP-16 (E) [45, 46] MMP-9 (E) [47, 48]

Flavanols

Catechins

Non-flavonoid

Chrysophanol Physcion Emodin

Silybin Silydianin epicatechin (EC) (−)-epicatechin-3-gallate (ECG), (−)-epigallocatechin (EGC) (−)-epigallocatechin-3-gallate (EGCG)

Milk thistle Green tea

MMP-2 (DI) [49] MMP-9 (DI) [49] MMP-12 (DI) [49] MMP-14 (DI) [49, 50]

Resveratrol

Red grape

Anthocyanidins

Grape seed

Proanthocyanidins

Cranberry

MMP-2 (DI) [51] MMP-9 (E) [52, 53] MMP-2 (E) [54] MMP-9 (E) [54] MMP-3 [55] MMP-9 [55] MMP-2 (E) [56] MMP-9 (E) [57] MMP-14 (DI) [58] MMP-9 (DI) [49] MMP-2 (E) [59] MMP-1 (E) [60] MMP-2 (E) [60] MMP-8 (E) [60] MMP-9 (E) [60] MMP-13 (E) [60] MMP-1 (DI) [61] MMP-2 (DI) [62] MMP-7 (DI) [61] MMP-9 (DI) [62] MMP-13 (DI) [61]

Curcumin

Non-polyphenol Saccharoids

Hyperforin Carrageenan Chitooligosaccharide

St. John’s Wort Red Seaweed

Neovastat (Squalamine)

Shark cartilage

E indicates that the reported method of action is on reducing expression while DI indicates direct inhibition of MMP activity

FDA approved for the treatment of glioblastoma multiforme, colorectal, renal, and lung cancer [74]. The same principles can now be applied for MMP inhibition (Table 3). Of the 23 family members, there is a large body of evidence demonstrating the critical roles for membrane bound MMPs in pericellular matrix degradation, invasion, and metastasis [81]. MMP-14, the archetypal membrane type MMP, can control tumor invasion, metastasis, and angiogenesis due to its ability to process extracellular matrix components and to control the activity of other proteases in addition to regulating cytokine and growth factor bioavailability and activity [82, 83]. MMP-14 has been shown to be particularly important in

facilitating the invasion of cancer cells through type I collagen rich extracellular matrices, and recent evidence identifies that this protease can recapitulate the Snail epithelial to mesenchymal (EMT) invasion program [84]. Based on this rationale, specific inhibition of MMP-14 would be efficacious for cancer treatment. Consistent with this hypothesis, inhibition of MMP-14 with monoclonal antibodies has been shown to be effective in preclinical animal models. Phage display and screening technology led to the isolation and characterization of a highly selective MMP-14 humanized antibody, DX-2400 [75]. The Ki of DX-2400 for MMP-14 is in the sub-nanomolar range compared to micromolar Ki for other MMPs. DX-2400

Cancer Metastasis Rev Table 3 MMP targeted antibodies that selectively neutralize MMP activity Antibody

Target

Application

Results

DX2400

MMP-14

In vitro and in vivo

14D10 9E8

MMP-13 MMP-14 non-catalytic domain

In vitro In vitro

Rat monoclonal GE-213

Pro and active MMP-7 MMP-9

In vitro In vitro

SDS3

MMP-2 MMP-9

In vitro and in vivo

Reduction in migration and invasion of endothelial cells, activation of proMMP-2. Reduction in tumor growth in MDA-MB-23 xenograft model and metastatic process in B16 melanoma to lung model [75] Inhibition of type II collagen production [76] Inhibition of MMP-2 activation and tendency to migration and invasion [77] Localization of MMP-7 protein in early stage tumors [78] Investigation of the role in local proteolysis of the extracellular matrix and in leukocyte migration as well as in bone osteoclastic resorption [79] Protects against inflammation and tissue damage in model of inflammatory bowel disease [80]

was found to selectively inhibit MMP-14 and the activation of pro MMP-2 without inducing or enhancing the expression of other MMPs, a phenomenon noted with broad-spectrum MMP inhibitors such as GM6001. DX-2400 effectively prevented the growth and angiogenesis of MDA-MB-231 and Her2-positive BT-474 xenografts and significantly contributed to the efficacy of paclitaxel and bevacizumab when applied in combination [75]. Phage display technology utilized to generate DX-2400 resulted in the generation of 70 distinct antibodies with a subset of 12 that could inhibit MMP-14 activity in the nanomolar range. These data demonstrate the power of antibody-based techniques in generating individual MMPs inhibitors. It is possible that specific inhibitors with lower Ki’s can also be potentially useful therapeutics. For example, complete ablation of MMP-14 could result in fibrosis of the soft tissue as noted in MMP-14 null mice. While studies in which rats were treated with high-dose DX-2400 for 1 month did not demonstrate musculoskeletal side effects, it is possible that longer-term treatments could be problematic with inhibitors that are ironically “too good.” Therefore, partial inhibitors of MMP-14 that prevent cancer progression but do not impact normal processes over the long term may be more clinically useful. In this regard, the monoclonal antibody, 9E8, blocks MMP-14 activation of MMP-2 but spares MMP-14 promigratory effects and proteolytic functions because the epitope is an 8-residue loop that is distal from the catalytic domain [77]. The catalytic domain of other nonmembrane bound MMPs can also be targeted using monoclonal antibodies (Table 3). Immunizing mice with synthetic compounds that resemble the catalytic zinc-histidine complex in the active site and the conformational epitopes on the surface of MMP-2 and MMP-9 makes it possible to produce monoclonal antibodies (SDS3 and SDS4) that are highly specific and function by mimicking the binding of TIMPS. Using this strategy, MMP-2 and -9 were both selectively

inhibited by monoclonal antibodies in a mouse model of inflammatory bowel disease but clearly these reagents could be extremely useful for the treatment of cancers in which MMP-2 and MMP-9 play a role [80]. Given the challenges involved in generating selective small molecule MMPIs that target the well-conserved catalytic domain, antibody-based strategies can circumvent this issue by targeting unique epitopes on individual MMPs. The efficacy and tolerability demonstrated by clinically successful antibody-based therapeutics provides a strong rationale for pursuing antibody-based MMPIs to treat cancer.

5 New tools to image MMP activity in vivo A major drawback of the previous MMPI-based clinical trials was the difficulty in determining if MMPIs were reaching the tumor microenvironment at sufficient concentrations to inhibit MMP activity. Therefore, imaging techniques that relay information on activity are required. The use of activity-based probes (ABPs) that are processed by selective MMPs to image cancer is one such approach [85, 86]. ABP construction typically utilizes peptide sequences that are selectively processed by an MMP of interest (Table 4). The sequences are covalently linked to dendrimer polyamido cores containing quenched near infrared fluorophores such as tetramethylrhodamine (TMR) that, once activated by MMPs, can facilitate deep tissue imaging. MMP-7 selective ABPs were developed using this approach but importantly included an additional quenched fluorescein label that acted as the optical sensor for MMP-7 activity while rhodamine served as an internal calibration control allowing for the detection of both the cleaved and intact probe. In vivo, using colon cancer cell lines that were positive and negative for MMP-7 expression, the selective cleavage of the systemically delivered proteolytic beacon in the MMP-7 expressing tumors was detected. As a proof of

Cancer Metastasis Rev Table 4 Commonly used MMP peptide sequences for the generation of MMP activatable beacons and theranostics MMP

Peptide sequence

Use

MMP-2

LS276-THP activatable NIR fluorescent probe for in vivo detection [87]

MMP-7

[(GPO)5GPK((7-methoxycoumarin-4-yl)acetyl) GPPG*VVGEK(2,4-dinitrophenyl)GEQ(GPO)5]3 GPAGLLG (AHX)RPLA*LWRS(AHX)-C

Detection [88] PB-M7NIR activatable NIR fluorescent probe for in vivo detection [89]

MMP-9 MMP-13 MMP-11 MMMP-14

GPLGLARK KGPRSLSGK GPLGGMRGLGK AAN-C(MeOBn)RM SLAPLGLQRR

Optical imaging, near-infrared (NIR) fluorescence [90] Fluorescence detection by FRET [91] In vivo detection [92] SM-P124 Fluorescence detection by FRET [93] Fluorescence detection by FRET [94]

principle, treatment of the mice with BB-94 significantly reduced (>60 %) the ability of the MMP-7 expressing tumors to process the MMP-7 selective proteolytic beacon. Similar approaches have selectively examined other MMPs such as MMP-13 [95]. Lipid-based micelles/nanoparticles have also been used to study MMP activity. MMP processing of selective peptides on near infrared bound micelles allowed for the accumulation of the micelles in areas of MMP activity in vitro and in vivo [96]. Stochastic optical reconstruction microscopy (STORM) was subsequently used to localize MMP activity in tissue sections. Similarly, active MMP-14 could also be detected on the cell surface using fluorophore tagged micelles displaying an inhibitory hydroxamate warhead bound selectively to MMP-14. The reagent, MP-3653, had a two and fourfold lower IC50 for MMP-14 when compared to membrane type MMPs, MMP24 and MMP-16, respectively. MP-3653 also allowed for the evaluation of the number of active MMP-14 molecules on the cell surface using fluorescence as a correlative readout and allowed the investigators to examine trafficking within the cell [97]. MMP activatable micelles can also be used to the study the cellular components of the tumor microenvironment. Studies have shown that altering the size of MMP-9 cleavable nanoparticles resulted in differential uptake and internalization by macrophages [98]. Other fluorescent-based techniques have utilized Cerenkov-induced imaging (SCIFI) to image MMP-2 activity in vivo. Fluorescently quenched MMP-2 selective probes were generated by anchoring carboxyfluorescein (FAM) to gold nanoparticles (AuNP) via the amino acid sequence, IPVSLRSG. Cleavage of the sequence by MMP-2 permits the biologically fluorescent conversion of Cerenkov luminescence that can subsequently be used to image MMP-2 activity in vivo [99]. In addition to fluorophores, MMP activity can be assessed with other imaging reagents. Using click chemistry, the luciferase enzyme can be maintained in a quenched state by binding to AuNP [100]. Insertion of an MMP-2 cleavable peptide allows for the activation of the luciferase and therefore, in the presence of D-luciferin, MMP-2 activity can be

monitored. These approaches to assess MMP activity are critical as readout for future MMP inhibitor-based clinical trials but independently could also be used as a diagnostic tool to image the in vivo tumor microenvironment.

6 Leveraging MMP activity as a theranostic approach for cancer treatment While the direct targeting of MMPs remains a rational approach for the treatment of cancer, utilizing heightened MMP activity in the tumor microenvironment to deliver MMP activatable prodrugs is also a novel means with which to specifically target the disease (Fig. 4). A major advantage of delivering chemotherapies in an activatable prodrug form is that it can reduce side effects. For example, patients treated with doxorubicin (DOX) and paclitaxel (PXL) can develop cardiotoxicity and peripheral neuropathy. To circumvent this, the conjugation of DOX and PXL to nanodendrons to generate prodrugs can potentially mitigate these systemic side effects [101]. Linking the DOX and PXL nanondendrons with an MMP-9 selective amino acid sequence allows for the activation of the prodrugs by MMP-9 overexpressing cancers. In this regard, treatment of lung cancer cell lines positive and negative for MMP-9 demonstrated the ability of MMP-9 to significantly enhance DOX and PXL cancer cell cytotoxicity. Similar studies have shown the feasibility of this approach using an MMP-2/9 activatable DOX conjugated reagent to treat MCF-7 breast cancer cells and patient derived primary lung cancer cell lines [102, 103]. MMP activatable nanoparticles, polymeric micelles, and liposomes can also be used to target cancer cells with DOX, PXL, and vincristine [104]. The active targeting strategy is mediated by incorporating ligands into the surface of nanocarriers that in turn bind to cognate receptors expressed specifically by the cancer cells [105]. Alternatively, antibodies to specific cancer targets can be used to guide the delivery of the particles. For example, trastuzumab emtansine is an antibodylinked chemotherapy that targets Her2, a receptor commonly

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A

POLYMER-CONTROLLED DELIVERY OF MMPI

MMP SELECTIVE LINKER

B

MAGNETIC NP

O DRUG HO

N

FLUORESCENT PROBE

O O HO

Fe3O4

H O y

x O

C

PLGA O

BIOLOGICAL TARGET

O

H

n

PEG

D Fig. 4 Theranostic and diagnostic applications for MMPs and MMPIs. a The delivery of hydroxamic-MMPIs to specific cancer sites can be achieved via dispersion within polylactic-co-glycolic acid (PLGA) cores of the nanoparticles. Surface functionalization with polyethylene glycol (PEG) can also enhance systemic circulation. b–d Alternatively, MMP cleavable polymer/linkers are useful in the progressive reduction in nanoparticle (NP) size, improving the enhanced permeability and retention (EPR) effect allows for the accumulation and internalization of NPs in cancer cells. Moreover, the inclusion of a peptide linker that is

selectively processed by an MMP can allow for the delivery of drugs and imaging reagents to the tumor microenvironment. For example, the introduction of Fe3O4 particles allows for the use of external magnetic fields to selectively target the cancer (b), the inclusion of quenched fluorophores activated upon processing by MMPs can confirm that drug cargos are being delivered directly to the tumor microenvironment (c) while MMP activity can also be used to improve the permeability of NPs displaying antibodies to specific cancer-associated targets (d)

expressed in breast cancer [106]. A similar approach could be employed to deliver MMPIs directly to the cancer microenvironment (Fig. 4). Further specificity can be mediated by the incorporation of prodrugs that remain in an inactive state within the nanoparticle until they are activated by a cancer-specific process. Successes in preclinical trials for the treatment of lung, gastric, colon, and cervical carcinomas, gliomas, and melanomas using nanoparticle approaches have been described [105]. By generating nanoparticles that display MMP selective sequences, the MMPs can process those peptides thus reducing the dimensions of the nanoparticles and allowing them to enter the cancer cell and deliver the chemotherapy pay-load. For example, by taking advantage of the elevated levels of MMP2 and -9 in glioblastoma, PXL-loaded nanoparticles, displaying the MMP-2 and -9 cleavable protamine, were utilized to deliver chemotherapies directly to gliomas in vivo [107]. This approach can also be used to target the tumor supporting microenvironment. MMP-14 expression by tumor-associated vasculature has also been used as a means to target the tumor microenvironment with activatable

nanoparticles. The peptide sequence GPLPLR can selectively bind to MMP-14 and therefore nanoparticles displaying this sequence and containing chemotherapies can be used to target the cancer blood supply [108]. It is possible that the inclusion of small molecule MMPIs in nanoparticles displaying MMP cleavable peptides could be developed (Fig. 4). This strategy could be useful in circumventing deleterious side effects noted with the systemic delivery of broad spectrum MMPIs. The inclusion of imaging molecules in prodrug design allows for the generation of theranostic tools that can provide a direct readout in regards to whether the therapy is specifically reaching the tumor-microenvironment and being processed by MMPs into an active form. EV1, a prodrug topoisomerase inhibitor that is activatable by MMP-9, was conjugated to quenched fluorescein isothiocyanate (FITC) [109]. Processing by MMP-9 therefore not only resulted in the activation of the topoisomerase inhibitor, but also in the activation of the FITC probe that in turn allowed for the visualization of MMP-9 in the in tumor microenvironment. Treatment of multiple myeloma cell lines positive (5TGMMvv) and negative (5TGMMvt) for MMP-9 expression demonstrated

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enhanced processing of the EV1 prodrug and increased fluorescence from the MMP-9 expressing myeloma cells [109]. Similar strategies could be used for imaging the in vivo distribution of multiple myeloma therapies such as melphalan and bortezomib. An important consideration for the development of theranostics is the incorporation of FDA approved imaging reagents. To this end, a recent report has incorporated FDA approved iron oxide (ferumoxytol) into an MMP-14 activatable prodrug, azademethylcolchicine (ICT) to yield a theranostic reagent. ICT can disrupt blood vessel patency upon processing by MMP-14 expressing endothelial cells. The injection of the iron oxide conjugated MMP-14 activatable prodrug into a mouse model of mammary tumorigenesis (MMTV-polyoma virus middle t antigen model) allowed for the MR imaging of MMP-14 activity in the tumor-microenvironment due to the accumulation of iron oxide and indirectly, as readout for the disruption of tumorassociated vasculature [110]. Importantly, these approaches focus on a “selectively” cleavable amino acid sequences but while these peptides may be selective in an in vitro setting it is possible that multiple proteases may have the ability to activate the nanoparticles in vivo. Innovative approaches to truly address the activity status and roles of individual MMPs in an in vivo context have been undertaken. For example, by substituting a unique non-conserved amino acid in the exosite region with a cysteine residue, MMP-12 and -14 enzymes have been engineered. The inclusion of the cysteine residue in the exosite facilitates the irreversible binding of MMP-12 and MMP-14 specific beacons to the catalytic domain of the enzyme. Importantly, the cysteine amino acid substitution does not interfere with enzyme substrate recognition thereby allowing the researchers to fully explore the activity status of individual MMPs in different settings [111]. These strategies will assist in defining the individual MMPs involved in disease settings so that selective theranostic reagents can be precisely delivered to the cancer microenvironment in order to prevent progression of the disease.

7 Conclusions Since the unsuccessful conclusion of several broad-spectrum MMP inhibitor trials over two decades ago, significant inroads in regards to the roles of individual MMPs in the context of different cancers have been made. We now know that MMPs can contribute to all aspects of cancer progression with some MMPs even playing protective roles. Furthermore, the number of identified MMP substrates, in particular non-matrix substrates, have expanded and revealed that MMPs are the key regulators of the bioavailability and bioactivity of a vast array of cytokines and growth factors. Leveraging this knowledge should allow for the inhibition of candidate MMPs with

highly specific MMP inhibitors. To this end, advances in chemistry, the discovery and refinement of natural compounds and new antibody technologies should allow for the generation of highly potent MMP inhibitors. Determining the efficacy/readout of MMPIs in vivo is also of critical importance and, the development of MMP activatable theranostics should greatly improve our ability in this regard to properly evaluate the MMP inhibition in vivo and ultimately facilitate the successful translation of those probes to the clinical setting for patient treatment. Acknowledgments We gratefully acknowledge the National Cancer Institute (RO1CA143094). We would also like to thank Barbara Fingleton at Vanderbilt University for her evaluation and critique of the manuscript.

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