COMPOSITIONS AND METHODS FOR TREATING CANCER

Abstract

Provided herein are compositions comprising a DR6 peptide; and methods for treating cancer and/or a tumor, including a platinum drug resistant tumor or cancer, in a patient in need thereof.

Claims

1. A composition comprising a DR6 peptide.

2. A composition comprising a conjugate comprising a DR6 peptide and a dye.

3. The composition of claim 2, wherein the conjugate is further attached to a functionalized human serum albumin to form an ARPNS probe.

4. The composition of claim 2, wherein the conjugate is attached covalently to a functionalized human serum albumin, natural or synthetic particle, to form an ARPNS probe.

5. The composition of claim 4, wherein the number of copies of the conjugate that are attached to the functionalized human serum albumin, natural or synthethic particle, to form an ARPNS probe is be selected from the group consisting of: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 and 100.

6. The composition of claims 3, wherein the ARPNS probe further comprises a functionalized group selected from the group consisting of: anticancer drugs, antibodies, radioactive materials, nucleotides, dyes and heavy metals.

7. The composition of claims 3, wherein the conjugate is attached to ARPNS probe by a cleavage site to allow controlled release of the DR6 peptide at the tumor site.

8. The composition of claim 7, wherein the cleavage site is the ADAM10 cleavage site.

9. The composition of claims 1, wherein the DR6 peptide is: -cdkc pagtyvsehc tntslrvcss cpvgtftr- (SEQ ID NO:1).

10. A method for treating a tumor or cancer in a patient in need thereof, said method comprising administering a therapeutically effective amount of the composition of claims 1.

11. The method of claim 10, wherein the tumor or cancer is platinum drug resistant.

12. The method of claim 10, wherein the cancer is selected from the group consisting of: pancreatic, colon, breast, prostate, lung, thyroid, testicular, leukemias, lymphomas, squamous cell carcinomas, nasopharyngeal carcinomas, and oral squamous cell carcinomas.

Description

BRIEF DESCRIPTION OF THE DRAWINGS

[0016] The structure and operation of the present invention will be understood from a review of the following detailed description and the accompanying drawings.

[0017] FIG. 1A: Western blots of homogenates from Pt resistant lines 2008/C13*5.23, A2780-CP and IGROV1-CP cells compared to sensitive parental lines 2008, A2780 and IGROV1. Rabbit polyclonal antibodies against human APP (top), APLP2 (middle) and APLP1 (bottom) and peroxidase conjugated goat antirabbit secondary antibodies were used. Monoclonal antibodies against tubulin were used for lane loading.

[0018] FIG. 1B: CCK-8 assay of A2780, A2780-CP and A2780-CP cells pre-incubated for 24 h with APP antisense oligonucleotides (A2780ONS) during a 1 h exposure to increasing concentrations of cDDP.

[0019] FIG. 2A: schematic view of exon-intron boundaries of the region between exons6-9 if APP pre-mRNA.

[0020] FIG. 2B: RT-PCR analysis of RNA from cDDP resistant cells 2008-C13*5.25 (1), A2780-CP (2) and IGROV-CP (3) cells using primers from the boundaries of exon 7 and exon 9 (top) and exon 7 (bottom band) after 30 cycles of amplification and resolving on 1% agarose gel.

[0021] FIG. 3: A 3-dimensional model of APP; presented in ref. [2]. APP consists of E1 domain, Kunitz protease inhibitor (KPI) domain, E2 domain, transmembrane domain (TMD) and intracellular domain. The acidic region and the region between the E2 and Aβ domains are predicated to have little secondary structure

[0022] FIG. 4. The overall strategy in the production of ARPNS

[0023] FIG. 5: Model of the DR6/APP signaling complex interaction at the neuronal surface (Xu et al [1]). Binding of APP-E2 and DR6 CRD domains induces DR6 dimerization and activation. The model was generated by combining the structure reported here of the APP-E2/DR6 complex with the dimeric APP-E1 structure (Protein Data Bank ID3KTM) (Dahms et al. 2010). The two molecules in the APP dimer are colored in yellow and green, while the two DR6 molecules are colored in magenta. The linker regions in the structure were depicted as dashed lines.

DETAILED DESCRIPTION

[0024] Provided herein are compositions comprising a DR6 peptide (-cdkc pagtyvsehc tntslrvcss cpvgtftr- SEQ ID NO:1). In particular embodiments, the composition can further comprise a conjugate comprising a DR6 peptide and a dye. In other embodiments, the conjugate can be further attached, preferably covalently, to a functionalized human serum albumin to form an ARPNS probe. In particular embodiments, either: 1-100, 1-90, 1-80, 1-70, 1-60, 1-50, 1-40, 1-30, 1-20, 1-10, 1-5, 1-2 copies of the conjugate are attached to the functionalized human serum albumin to form an ARPNS probe. In other embodiments, the number of copies of the conjugate that are attached to the functionalized human serum albumin to form an ARPNS probe can be selected from the group consisting of: 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95 and 100.

[0025] n other embodiments, the ARPNS probe further comprises carrier molecules other than human serum albumin including natural or synthetic particles. The ARPNS probe can contain a functionalized group selected from the group consisting of anticancer drugs, antibodies well-known in the art, radioactive materials, nucleotides, dyes (e.g., fluorescent and near fluorescent, and the like) and heavy metals (e.g., molecules that can be detected by various imaging machines).

[0026] Exemplary anti-cancer drugs include: alkylating agents (e.g., cisplatin, chlorambucil, procarbazine, carmustine, and the like), antimetabolites (e.g., methotrexate, cytarabine, gemcitabine, and the like), anti-microtubule agents (e.g., vinblastine, paclitaxel, and the like), topoisomerase inhibitors (e.g., etoposide, doxorubicin, and the like), cytotoxic agents (e.g., bleomycin, mitomycin, and the like).

[0027] Exemplary anti-cancer drugs include: abciximab (Reopro), adalimumab (Humira, Amjevita), alefacept (Amevive), alemtuzumab (Campath), basiliximab (Simulect), belimumab (Benlysta), bezlotoxumab (Zinplava), canakinumab (Ilaris), certolizumab pegol (Cimzia), cetuximab (Erbitux), daclizumab (Zenapax, Zinbryta), denosumab (Prolia, Xgeva), efalizumab (Raptiva), golimumab (Simponi, Simponi Aria), inflectra (Remicade), ipilimumab (Yervoy), ixekizumab (Taltz), natalizumab (Tysabri), nivolumab (Opdivo), olaratumab (Lartruvo), omalizumab (Xolair), palivizumab (Synagis), panitumumab (Vectibix), pembrolizumab (Keytruda), rituximab (Rituxan), tocilizumab (Actemra), trastuzumab (Herceptin), secukinumab (Cosentyx), ustekinumab (Stelara), and the like.

[0028] In certain embodiments, the conjugate is attached to ARPNS probe by a cleavage site, preferably the ADAM10 cleavage site, to allow controlled release of the DR6 peptide at the tumor site. In other embodiments in may contain other cleavage sites and linkers including various enzymes and pH sensitive linkers of various sizes and qualities well-known in the art. In a particular embodiment, the DR6 peptide corresponds to: -cdkc pagtyvsehc tntslrvcss cpvgtftr—(SEQ ID NO:1).

[0029] Also provided herein are methods for treating cancer and/or a tumor, including a platinum drug resistant tumor or cancer, in a patient in need thereof, said method comprising administering and effective amount of an invention composition provided herein. In particular embodiments, the cancer is selected from the group consisting of: pancreatic, colon, breast, prostate, lung, thyroid, testicular, leukemias, lymphomas, squamous cell carcinomas, nasopharyngeal carcinomas, and oral squamous cell carcinomas.

[0030] After reading this description it will become apparent to one skilled in the art how to implement the invention in various alternative embodiments and alternative applications. However, although various embodiments of the present invention will be described herein, it is understood that these embodiments are presented by way of example only, and not limitation. As such, this detailed description of various alternative embodiments should not be construed to limit the scope or breadth of the present invention as set forth in the appended claims.

[0031] The unique role of APP in survival, Fe homeostasis, and Pt resistance, its absence from non-neural tissues, its tumor specific splice variants added to the well characterized properties of this molecule, supports APP as a candidate for diagnostic and therapeutic exploitation. Based on the interactions of APP with its many partners, we designed the ADR6N1probe (or APP-binding molecule) for in vivo targeting of APP-expressing Pt resistant tumor cells. In accordance with the present invention, it has been found that the ADR6N1 probe can recognize APP in vivo and that its validation as a in vivo tracer of the Pt resistant ovarian tumor will provide a much needed tool for detection, monitoring treatment of Pt resistant ovarian tumors [6].

[0032] Design of ARPNS Probe. The overall strategy for the construction of the ARPNS probe is described in FIG. 4. The goal in this strategy is to construct a probe that contains many copies of the tumor detection peptide and the dye attached covalently to a carrier. We identified a 3.5 KDa peptide from the extracellular domain of the DR6/TNFRSF21 protein; the peptide binds APP with high affinity both in vivo and in vitro. To allow in vivo detection we will conjugate the DR6 peptide with the near infrared (NIR) dye IRDye800CW. In the next step, 18-20 copies of the DR6-IRDye800CW conjugate are covalently attached to a functionalized human serum albumin (H-AS) molecule to generate the ARPNS (APP Recognition Peptide-NIR-Serum albumin) probe. The ARPNS is used for in vivo and in vitro detection of APP expressing cells. The size of ARPNS is relatively small (expected to be ˜12-15 nm), which is suitable for deep penetration into tumor by Enhanced Permeation and Retention (EPR) [127, 128]. The probe is also amenable to addition of other functional groups, such as, for example, those functional groups selected from the group consisting of: anticancer drugs [129-131], antibodies [132-135], radioactive materials [136-139], and nucleotides. In particular embodiments, the ADAM10 cleavage site is added to the probe to allow controlled release of the peptide at the tumor site.

[0033] The DR6 peptide corresponding to amino acids -cdkc pagtyvsehc tntslrvcss cpvgtftr- (SEQ ID NO:1) is a 3.5 KDa fragment of the extracellular domain of the death receptor protein DR6; this domain was shown to bind APP in vivo and in vitro [1, 140, 141]. The peptide spans the (CRD1)f domain of DR6, is a member of the tumor necrosis factor receptor family. The protein can be induced by ROS via NFKB [142] and is a candidate biomarker of ovarian [143, 144], melanoma [145] and sarcoma [146] cancers. DR6 functions in metastasis [147], tumor induced necrosis [148, 149], and caspase 3-mediated apoptosis [140]. DR6 binding region in APP is within he E2 domain [1, 140, 141]. The binding may trigger events that range from pathfinding to cell death [140, 150] (FIG. 5).

[0034] While many other proteins bind APP [151] and the binding of several proteins such as F-spondin [152], SLIT1, SLIT2 [153], contactins 2, 3, 4 [151, 154] has been well documented, the DR6 interaction with APP is one of the best characterized, including the identities of the interacting amino acid residues on both proteins [1]. In addition, DR6 does not seem to bind any other extracellular or membrane protein, thus provides the specificity that we need for targeting APP expressing proteins. Aβ binding peptides such as affibodies [155] and anticalins [156] are also an option, but most of these peptides are specific to the aggregated Aβ peptides.

[0035] NIR fluorophore IRDye800CW is near infrared dye that is commonly used for in vivo imaging. The dye is attached to the C-terminus of the DR6 peptide and can be cleaved by the ADAM10 protease.

[0036] Human serum albumin (H-SA) is labeled with Alexa Fluor 633 dye on its single cysteine 34 to allow tracing of the stability of the conjugates; H-SA used as a carrier will allow attachment of multiple copies of the DR6-dye conjugate as well as serve to protect the probe from proteolysis in plasma or engulfment by phagocytes; as a carrier HSA is ideal as a natural, non-toxic and non-immunogenic protein.

[0037] Encapsulation with polyethylene glycol is considered if the probe becomes immunogenic or is endocytosed by tissue and blood macrophages.

EXAMPLES

Materials and Methods

[0038] The objective of this initial study is to assess the feasibility of using ARPNS as an in vivo probe for Pt resistant cells that express the APP biomarker. The use of DR6 peptide as a binding partner of APP will provide another layer of specificity, because it does not have any other extracellular partners; the provision of ADAM10 peptide at the flanking regions of the DR6 peptide will ensure the release of the peptide and the dye at the tumor site. The ADAM10 is highly expressed in A2780 cells as our Western blotting data indicates.

[0039] For binding studies, we have made extensive use of the A2780 cell line, which we have characterized in different experimental settings. This cell line was used to produce the A2780-APP-LUC and A2780-LUC sublines by introducing lentiviral constructs of a full length APP751 cDNA-tagged with the luciferase peptide and the the luciferase tag alone using pLenti CMV Puro LUC (Addgene Watertown, Mass.).

Example 1: Demonstrate the Specify of ARPNS for Pt Drug Resistant Tumors Cells In Vitro.

[0040] In this example we will first (1) assemble the ARPNS probe and determine its physicochemical properties; and then (2) assay binding between ARPNS and purified ectodomain of APP, using ELISA assay, and between APP and ARPNS using cell surface binding assay, using A2780-APP-LUC and A2780-LUC cells. The A2780-APP-LUC and A2780-LUC is used to (3) assay the cytotoxicity of ARPNS; and (4) the cellular uptake of ARPNS.

[0041] (1) Assembly of the ARPNS probe and determination of its physicochemical properties: The functional moiety in ARPNS is the DR6 peptide; this peptide has no known post-translational modification except for N82 glycosylation that appears to fall outside of its binding domain with APP [1]. to achieve correct pos-translational modification of the peptide we will express the peptide in Sf9 cells using a baculoviral system.

[0042] (1a) Expression of DR6 peptide (corresponding to -cdkc pagtyvsehc tntslrvcss cpvgtftr- (SEQ ID NO:1)): A 96 base pair DNA fragment of DR6 cDNA that corresponds to the amino terminal sequences between residues Cys67-Arg98 has been cloned in the pTOPO-TA vector. After PCR amplification of this sequence and addition, on each of its N and C terminal ends, of the hqklvf peptide motif for ADAM10 cleavage site (found in APP ectodomain) [157] the sequence is cloned in the baculoviral vector HBM TOPO and expressed as a secreted protein in Sf9 cells (Thermo Fisher Scientific, Carlsbad, Calif.). The secreted His-tagged peptide is purified on Ni columns and excised by TEV [158] and after HPLC purification [159], it is conjugated and linked with the NIR dye IRDye800CW (LiCor Biosciences, Lincoln, Nebr.).

[0043] (1b) Attachment of DR6- peptide to IRDye800CW. The DR6 is first reacted with the GMBS (N-γ-maleimidobutyryl-oxysuccinimide ester) and then reacted with the IRDye800CW-MAL on a 1:1 ration. The construct is column purified and conjugated with the human serum albumin (H-SA) (Sigma-Aldrich, St. Louis Mo.).

[0044] (1c) Attachment of the DR6-peotide-NIR-dye conjugate to H-SA. H-SA is first reacted with the bifunctional liner succinimidyl 3-(2-pyridyldithio) propionate (SPDP) at a ratio of 1:25 molar ratio of protein/linker, it is then purified and the number of linked SPDP conjugates determined. The H-SA-SPDP is linked to DR6-thiol group of IRDye800CW at a 1:20 molar ratio of H-SA to DR6-IRDye800CW. Linkers and reagents are from Thermo Fisher Scientific, Carlsbad, Calif.).

[0045] (1d) Determination of the physicochemical properties of ARPNS in vitro. The probe is purified by HPLC and its size and molecular weight determined; the size of the probe will also be confirmed along with ζ potential determined using a Zetasizer Nano (Malvern Instruments, Westborough, Mass., USA) at 25° C.

[0046] (1e) Assessing the stability of ARPNS. Dialysis PBS plus 20% bovine serum is performed for 4-12 h at 37° C. and samples from both inside the dialysis bag and the chamber are taken in regular intervals to assess the fluorescence of NIR with a UV-3600 Plus UV-Vis-NIR Spectrophotometer.

[0047] (2) Assessment of the specificity of interaction between ARPNS and the ectodomain pf APP using ELISA and cell surface binding assays.

[0048] (2a) Assessment of the specificity of interaction between ARPNS and APP using ELISA assays. These experiments are performed in 96 well plates coated with the purified ectodomain of APP [150]. Binding is performed for 24 h at 4° C. after a 2 h blocking with PBS plus 1% BSA. Serial dilutions of ARPNS are used for incubation. Detection of the bound probe is made after incubation for 1 h with an HRP conjugated anti-DR6 polyclonal antibodies (R&D systems, Minneapolis, Minn.) and then treatment with HRP color reagents (R&D Systems) followed by determining the signal at 450 nm with a Tecan plate reader.

[0049] (2b) Assessment of the specificity of interaction between ARPNS APP on the cell surfaces. This assay is performed using cell lines A2780-APP-LUC and A2780-LUC. Cells are incubated with different dilutions of ARPNS in binding buffer with 2% BSA for 2 h on ice, and 20 min in 37oC chamber. Cells are then fixed with 3% formaldehyde and reacted with fluorescein conjugated polyclonal antibodies against DR6 (AF144, R&D Systems Minneapolis, Minn.) for 1 h and then washed and the levels of fluorescence determination by a Tecan plate reader [140, 150].

[0050] (2c) Assessment of cytotoxicity. One day after seeding A2780-APP-LUC and A2780-LUC cells in 96-well plates at 8×104 cells/well, cells are treated with different dilutions of ARPNS for 5 days after which they are assayed with Count Kit 8 (CCK-8) (Dojindo, Gaithersburg, Md.) reagents using absorption at 450 nm and a Tecan plate reader [160].

[0051] (2d) Assessment of cellular uptake: A2780-APP-LUC and A2780-LUC cells are incubated with appropriate dilutions of ARPNS for 1-4 h after which they are fixed with 3% formaldehyde and stained with antibodies against APP, DR6, Rab5, Rab7 (for endosome) and lysotracker red (lysosome) Hoechst 33342 dye (for nuclei) and then reacted with secondary fluorescent antibodies [161]. Cells are imaged with a deconvoluting confocal microscope.

[0052] The results of Example 1 indication that ADR6NI is suitable as an in vivo indicator of Pt drug resistance.

Example 2: Demonstrate the Specificity ARPNS as an In Vivo Targeting Tool for Pt Drugs Resistant Tumors Using a Xenograft Mouse Model.

[0053] These experiments begin upon optimizing the binding of APP to ARPNS and adjusting the ARPNS probe, the A2780-APP-LUC and A2780-LUC cells to achieve maximum specificity. All animal studies are performed with the approval of the Animal Research Committee and according to the institutional guidelines at the Explora BioLabs, San Diego, Calif., where the mouse is housed. We will (1) establish mouse xenograft model using the intraperitoneal inoculation of A2780-APP-LUC and A2780-LUC cells; (2) select a suitable route of delivery for the ARPNS probe; and (3) assay binding between ARPNS and APP in vivo, using in vivo imaging, histological and biochemical analysis. Nu/Nu mice are immune compromised and are ideal for both tumor growth as well as the integrity of the probe that is less likely to be taken up by defective macrophages in these animals.

[0054] (1) Establishment of mouse xenograft model; 5-6-weeks old female Nu/Nu mice (Charles River, San Diego, Calif.) are inoculated in the peritoneal cavity with 2X106 of either A2780-APP-LUC or A2780-LUC and tumor growth is monitored with an IVIS 200 imager (Caliper Life Sciences) on isoflurane anesthetized mice. After 3 or 4 days, mice with engrafted tumor are randomly divided into control (receiving saline) and experimental groups (receiving ARPNS). Injections begin when tumors reach about 120 mm3 in diameter. The use of A2780-LUC cells is to test for non-specific binding of the probe; if the initial experiments show no in vivo association between these cells and the probe, we will exclude this set from the experiment and focus on characterizing the binding of A2780-APP-LUC xenografts with the probe in detail.

[0055] (2) Selection of route of ARPNS delivery. HSA conjugates are usually suitable for both intravenous (IV) and intraperitoneal injection (IP); to assess the advantages and disinvites of of IV vs. IP for the case of ARPNS, a single injection of 100 mg/Kg of body weight is used. Animals are imaged post-injection at 1, 3, 6 and 24 h and sacrificed at 24 h. The route of injection that produces the highest level of drug in tumors, and the lowest in different organs is used.

[0056] (3) Determination of maximum tolerated doses (MTD, is defined as the maximum dose of a drug that does not cause death or >20% body weight loss). MTF is determined by dose escalation from 25, 50, and 150 mg/Kg probe after 4 weeks of daily injection with 25, 50 and 150 mg of ARPNS/Kg body weight.

[0057] (4) Analysis of peritoneal cavity washes. After sacrifice, the peritoneal cavity is rinsed twice with PBS and the fluid collected in EDTA tubes; trypan blue cell counts and FACS analysis are performed to determine the number of necrotic and sloughed tumor cells and ARPNS levels in the cavity; the data is examined by a licensed veterinary pathologist at Histology and Comparative Pathology Shared Resource at UCSD.

[0058] (5) Terminal tissue collection and measurements of tumor burden. After sacrifice, tumors are removed, and measured for weight and volume. Blood samples are collected by cardiac puncture and blood smears prepared for testing with the Siemens Advia™120 hematology analyzer Idexx for General Panel (clinical blood chemistry and biochemistry); lung, heart, liver, spleen, kidneys, ovaries, uterus and brain are removed, weighed, assessed for damage, and their NIR and DR6 contents determined by spectrophotometry and Western blotting respectively; tissues are stored in liquid nitrogen.

[0059] (6) Histology of xenografts. All histology work is performed at the Histology and Comparative Pathology Shared Resource at UCSD. Tumors and other tissues (to be determined depending on distribution data) are fixed in 10% formalin, embedded in paraffin and sectioned at 5 μm thickness. Routine staining is with eosin hematoxylin. A board-certified veterinary pathologist will determine the degrees of vascularization, necrosis, number and type of macrophage, neutrophil, lymphocytes and eosinophils in tumors. Interaction of ARPNS with APP is determined with staining tissue sections with antibodies against APP and DR6 and localization of the NIR fluorescence.

Statistical Analysis

[0060] All in vitro experiments are repeated at least 3 times with 3 or more samples per data point; animal studies is performed on 3-6 animals per condition. Data is presented as mean±standard error of mean (SEM). Test of significance with be with Student's t-test with significance level set at P<0.05. Analysis of variance for two or more groups is by ANOVA. GraphPad Prism4 program (GraphPad Software, San Diego, Calif.) is used for calculations. Pharmacokinetic analysis will use the WinNonlin software, version 6.2 (Pharsight Corp., Sunnyvale, Calif.).

[0061] The above description of the disclosed embodiments is provided to enable any person skilled in the art to make or use the invention. Various modifications to these embodiments will be readily apparent to those skilled in the art, and the generic principles described herein can be applied to other embodiments without departing from the spirit or scope of the invention. Thus, it is to be understood that the description and drawings presented herein represent a presently preferred embodiment of the invention and are therefore representative of the subject matter which is broadly contemplated by the present invention. It is further understood that the scope of the present invention fully encompasses other embodiments that may become obvious to those skilled in the art and that the scope of the present invention is accordingly not limited.

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