NL2011676C2

NL2011676C2 - Compositions comprising polyethylene glycol for use in the therapy of egfr-dependent cancers.

Info

Publication number: NL2011676C2
Application number: NL2011676A
Authority: NL
Inventors: Ian David Cox; Christopher Alexander Hewson; Hemant K Roy; Ramesh K Wali
Original assignee: Univ Northshore Healthsystem; Norgine Bv
Priority date: 2012-10-26
Filing date: 2013-10-25
Publication date: 2015-04-07
Also published as: AR093154A1; TW201436799A; NL2011676A; WO2014066797A1

Abstract

Disclosed are compositions comprising polyethylene glycol (PEG) having a weight average molecular weight of 800 or greater and a concentration of 30mg/ml or greater for use in preventing and/or treating epidermal growth factor receptor (EGFR) dependent cancers, other than head and neck squamous cell carcinoma (HNSCC). Methods of treating and/or preventing EGFR-dependent cancers are also disclosed.

Description

Compositions comprising Polyethylene Glycol for use in the therapy of EGFR-dependent cancers.

The present invention concerns compositions for use in the prophylaxis and/or treatment of epidermal growth factor receptor (“EGFR”)-dependent cancers. The present invention also concerns methods for preventing and/or treating such cancers. Other aspects, objects and advantages of the present invention will be apparent from the description below.

Background of the Invention.

In PCT/US2012/035434 there is disclosed, inter alia, methods for preventing and/or treating HNSCC comprising the step of administering an effective amount of polyethylene glycol (PEG).

Summary of the Invention.

The present invention concerns compositions and methods for preventing and/or treating EGFR-dependent cancers as described further below.

The term “EGFR-dependent cancers” means cancers whose initiation and/or proliferation and/or invasiveness is responsive to treatment that interferes with the EGFR signaling pathway. EGFR-dependent cancers include cancers that over-express EGFR. EGFR-dependent cancers also includes EGFR surface expressing cancers demonstrating inappropriate activation (e.g. ligand independent activation) of the EGFR signaling pathway.

An EGFR-dependent cancer can be determined, for example, by comparing the proliferation of the cancer in the presence and absence of epidermal growth factor (EGF). Those cancers which demonstrate increased proliferation and/or invasiveness in the presence (compared to the absence) of EGF may be determined to be “EGFR-dependent cancers”. EGFR-dependent cancers may also be determined by observing a decrease in initiation and/or proliferation and/or invasiveness of the cancer following treatment with an agent (such as cetuximab) that targets and interferes with EGFR signaling.

Certain human cancers are known to typically be EGFR-dependent cancers. Squamous cell carcinomas (SCC) and adenocarcinomas (AC) refers to cancers that originate from the epithelium. SCC and/or AC are frequently EGFR-dependent (Lee S M; Thorax 2006 Feb; 61(2):98-99). EGFR signaling is implicated in bladder, breast, cervical, colorectal (CRC), endometrial, gastric, lung, ovarian cancer (see table 1, Sharafinski et al; Head Neck: 2010 October;32(10): 1412-1421). EGFR has also been proposed as a putative target in esophagogastric cancer (see Okines A et al; Nat.Rev Clin Oncol. 2011 Apr 5; 8(8):492-503), pancreatic cancer (see Ciardiello F et al; N Engl J Med 2008; 358:1160-74), anal cancer (Paliga A.A et al; J Clin Oncol 29: 2011 (suppl 4; abstr 412)), renal cancer (Salomon D.S et al; Crt.Rev Oncol. Hematol 1995; 19:183-232), non-melanoma skin cancers such as basal cell carcinomas and squamous cell carcinoma of the skin (e.g. cutaneous squamous cell carcinoma, cSCC, see Spallone G et al; Cancers 2011, 3, 2255-2273), melanomas, such as skin melanomas (see Boone B et al, J Cutan Pathol. 2011 Jun; 38(6):492-502). Henceforth, these cancers are referred to collectively as “EGFR cancers” or “EGFR cancer”.

The present invention provides compositions and methods for the treatment and/or prevention of any one of these aforementioned EGFR cancers. The present invention does not include within its scope, head and neck squamous cell carcinoma (HNSCC), which includes squamous cell carcinoma of the lip and esophagus.

In accordance with the present invention there is provided a composition for use in preventing and/or treating a EGFR-dependent cancer (such as any one of the EGFR cancers mentioned above), the composition comprising polyethylene glycol (PEG) at a concentration of 30mg/ml or greater wherein the PEG has a weight average molecular weight (Mw) of 800 daltons or greater.

In accordance with the present invention there is provided a method for preventing and/or treating a EGFR-dependent cancer (such as any one of the EGFR cancers mentioned above) in a subject, the method comprising administering to the subject an effective amount of the composition of the invention. Compositions for use in such a method are also provided.

In another embodiment, the present invention provides a method for preventing and/or treating a EGFR-dependent cancer (such as any one of the EGFR cancers mentioned above) in a subject comprising administering to the subject an effective amount of the composition of the invention, the composition comprising PEG at a concentration of 30mg/ml or greater, wherein PEG preferably of 800 daltons or thereabout to 20,000 daltons or thereabout, for example 2000 daltons or thereabout to 15,000 daltons or thereabout, more preferably 3000 or thereabout to 12,000 or thereabout, for example, 3000 daltons or thereabout to 10,000 daltons or thereabout, most preferably 3200 daltons or thereabout to 9000 daltons or thereabout (e g. 3000 daltons or thereabout to 4000 daltons or thereabout, 3500 daltons or thereabout to 7000 daltons or thereabout or 7000 daltons or thereabout to 9000 daltons or thereabout). In most preferred embodiments, PEG has a Mw of 3350 daltons or thereabout, 4000 daltons or thereabout, 8000 daltons or thereabout, 10000 daltons or thereabout, 15000 to 20000 daltons or thereabout. Of these, PEG having a Mw of 8000 daltons or thereabout or 10,000 daltons or thereabout is particularly preferred.

In another embodiment, the invention provides a composition for use in the prophylaxis and/or treatment of a EGFR-dependent cancer as described in various aspects and embodiments of the invention herein, the composition comprising (e.g. as its sole therapeutically active constituent) PEG having a Mw as described herein at a concentration of 30mg/ml or greater.

In an embodiment, the present invention provides a method for preventing and/or treating a EGFR-dependent cancer in a subject comprising topically administering to said subject an effective amount of the composition of the invention. Compositions for use in such a method are also provided.

In accordance with another embodiment, the present invention provides a method for reducing or suppressing an EGFR-dependent cancer initiation and/or proliferation and/or invasiveness in a subject comprising topically administering to the region of the subject afflicted with a pre-existing EGFR-dependent cancer and/or a pre-malignant lesion, an effective amount of the composition of the invention. Compositions for use in such a method are also provided.

In accordance with another embodiment, the present invention provides a method for preventing and/or treating a EGFR-dependent cancer (such as any one of the EGFR cancers mentioned above) in a subject comprising locoregionally administering to the subject an effective amount of the composition of the invention. Compositions for use in such a method are also provided.

The present invention further provides a composition for locoregional use in the prevention and/or treatment of a EGFR-dependent cancer (such as any one of the EGFR cancers mentioned above) in a subject afflicted with said disease wherein the composition comprises PEG as described herein.

It is further contemplated that in an embodiment of the present invention, a method for preventing and/or treating a EGFR-dependent cancer in a subject, wherein an effective amount of the composition of the invention is administered to the subject from 1 to 5 time(s) a day, preferably 2 to 4 times a day, more preferably 3 times a day.

Compositions for use in such a method are also provided.

In accordance with a further embodiment, the present invention provides a method for reducing or inhibiting EGFR surface expression and/or phosphorylation of the receptor in a EGFR-dependent cancer of a subject, the method comprising administering to the subject an effective amount of the composition of the invention. Compositions for use in such a method are also provided.

In another embodiment, the present invention comprises a method for preventing and/or treating a EGFR-dependent cancer (such as any one of the EGFR cancers mentioned above) in a subject which method comprises co-administering to the subject an effective amount of the composition of the invention with an effective amount of one or more additional therapeutic agent(s). Compositions for use in this method optionally further comprising the one or more additional therapeutic agent(s) are also provided.

In another aspect of the invention there is provided a method for preventing and/or treating a EGFR-dependent cancer in a subject which method comprises administering to said subject: (a) an effective amount of a therapeutic agent such as an anti-EGFR agent (for example an anti-EGFR antibody such as cetixumab); (b) an effective amount of a composition of the invention.

In some embodiments of this aspect of the invention, step (a) occurs before step (b). In other embodiments of this aspect of the invention, step (a) occurs after step (b). In further embodiments of this aspect of the invention, step (a) and step (b) occur concurrently.

In another embodiment of the invention, there is provided a method for preventing and/or treating a EGFR-dependent cancer (such as any one of the EGFR cancers mentioned above) in a subject in remission of the EGFR-dependent cancer, the method comprising administering to the subject an effective amount of the composition of the invention. The subject may be in partial or complete remission. Compositions for use in such a method are also provided.

In another embodiment of the invention there is provided a method for ameliorating (such as preventing) the recurrence of a EGFR-dependent cancer (such as any one of the EGFR cancers mentioned above) in a subject in remission of that disease, the method comprising administering to the subject an effective amount of the composition of the invention. Compositions for use in such a method are also provided.

In another embodiment of the invention there is provided a method for preventing and/or treating a metastatic EGFR-dependent cancer (such as any one of the EGFR cancers mentioned above) in a subject which method comprises administering to the subject an effective amount of the composition of the invention. Compositions for use in such a method are also provided.

In another embodiment of the invention there is provided a method for preventing and/or treating a locally advanced EGFR-dependent cancer (such as any one of the EGFR cancers mentioned above) in a subject which method comprises administering to the subject an effective amount of compositions of the invention. Compositions for use in such a method are also provided.

In another aspect of the invention there is provided a method for regressing a EGFR-dependent cancer (such as any one of the EGFR cancers mentioned above) in a subject which method comprises (a) administering an effective amount of a composition of the invention. Compositions for use in such a method, such as described herein, are also provided. In some embodiments of this aspect of the invention, the EGFR-dependent cancer is a squamous cell carcinoma (other than HNSCC) such as a SCC of the skin (e.g. cSCC) or anus. Preferably, the squamous cell carcinoma over-expresses EGFR. The EGFR expression status of the squamous cell carcinoma may be determined according to standard methods, techniques and kits such as described herein.

In an embodiment of this aspect of the invention, the method further comprises (b) resecting and/or ablating the EGFR-dependent cancer and/or administering an effective amount of a therapeutic agent. In this embodiment of the invention, step (b) may occur after step (a). By regressing the EGFR-dependent cancer, the present invention may reduce the degree of trauma or treatment related adverse events to the subject resulting from subsequent therapeutic procedures.

In another aspect of the invention, there is provided a method for preventing and/or treating a EGFR-dependent cancer (such as any one of the EGFR cancers mentioned above) in a subject comprising; (a) resecting and/or ablating one or more EGFR-dependent cancers; (b) administering to the subject an effective amount of the composition of the invention.

In one embodiment of this aspect of the invention, step (a) occurs before step (b). In another embodiment, step (b) occurs before step (a).

The invention further provides the use of PEG having a Mw of 800 daltons or greater and a concentration of 30mg/ml or greater in the manufacture of a medicament for the treatment and/or prophylaxis of a EGFR-dependent cancer, as described in various aspects and embodiments herein.

The invention further provides the use of PEG having a Mw of 800 daltons or greater and a concentration of 30mg/ml or greater as described in various aspects and embodiments herein in the manufacture of a medicament, for regressing a EGFR-dependent cancer such as a squamous cell carcinoma (other than HNSCC), for example, cSCC or anal cancer, or an adenocarcinoma.

In some embodiments of the invention according to any of the embodiments and aspects described herein, the EGFR-dependent cancer is a EGFR cancer selected from the group consisting of: bladder, breast, cervical, colorectal, endometrial, gastric, lung (e.g. nonsmall cell lung cancer, NSCLC), ovarian, esophagogastric, pancreatic, anal, renal, nonmelanoma skin cancers such as basal cell carcinoma and/or squamous cell carcinoma of the skin (e.g. cSCC), melanoma cancer of (for example) the skin. Preferably the EGFR-dependent cancer is a gastric, esophagogastric, colorectal, anal or non-melanoma skin cancer such as basal cell carcinoma or squamous cell carcinoma of the skin. Of these, colorectal cancer (CRC) and non-melanoma skin cancer is particularly preferred.

In some other embodiments of the invention according to any of the embodiments and aspects described herein, the EGFR-dependent cancer is a squamous cell carcinoma (other than HNSCC, including the lip and the esophagus) and/or an adenocarcinoma.

Brief Description of the Figures

Figure 1

Figure 1 depicts PEG-induced cytotoxicity in the human SK-MEL-2 cell-line after 24 hours incubation with (A) PEG-3350, (B) PEG-8000 and (C) PEG-10,000. The effects of the PEG compounds were calculated and plotted as percentage inhibition compared to untreated cells. Erlotinib did not produce consistent cytotoxic effects and 10 μΜ doxorubicin produced a sub-maximal effect (51% inhibition; data not shown). PEG-3350, -8000 and -10,000 induced cytotoxicity with potencies of 31.0 (± 2.7), 12.1 (± 2.0) and 8.1 mM (± 0.3), respectively. Maximum effects for PEG-3350, -8000 and - 10,000 were 87, 88 and 86%, respectively. Data are presented as the mean of n=3 (in triplicate) experiments ± standard error of the mean (SEM). IC50 values are quoted as the mean of n=3 experiments, ± standard error of the mean (SEM).

Figure 2

Figure 2 depicts PEG-induced cytotoxicity in the human SK-MEL-2 cell-line after 72 hours incubation with (A) PEG-3350, (B) PEG-8000 and (C) PEG-10,000. The effects of the PEG compounds were calculated and plotted as percentage inhibition compared to untreated cells. Erlotinib did not produce consistent cytotoxic effects and 10 μΜ doxorubicin produced a sub-maximal effect (84% inhibition; data not shown). PEG-3350, -8000 and -10,000 induced cytotoxicity with potencies of 27.9 (± 3.8), 13.3 (± 0.2) and 8.4 mM (± 0.6), respectively. Maximum effects for PEG-3350, -8000 and - 10.000 were 96, 95 and 95%, respectively Data are presented as the mean of n=3 (in singlicate) experiments ± standard error of the mean (SEM). IC50 values are quoted as the mean of n=3 experiments, ± SEM.

Figure 3

Figure 3 depicts PEG-induced cytotoxicity in the human MKN-45 cell-line after 24 hours incubation with (A) PEG-3350, (B) PEG-8000 and (C) PEG-10,000. The effects of the PEG compounds were calculated and plotted as percentage inhibition compared to untreated cells. Erlotinib did not produce consistent cytotoxic effects and 10 μΜ doxorubicin produced a sub-maximal effect (59% inhibition; data not shown). PEG-3350, -8000 and -10,000 induced cytotoxicity with potencies of 32.9 (± 8.3), 12.7 (± 3.3) and 5.7 mM (± 0.7), respectively. Maximum effects for PEG-3350, -8000 and - 10.000 were 90, 91 and 91%, respectively. Data are presented as the mean of n=3 (in triplicate) experiments ± standard error of the mean (SEM). IC50 values are quoted as the mean of n=3 experiments, ± SEM.

Figure 4

Figure 4 depicts PEG-induced cytotoxicity in the human MKN-45 cell-line after 72 hours incubation with (A) PEG-3350, (B) PEG-8000 and (C) PEG-10,000. The effects of the PEG compounds were calculated and plotted as percentage inhibition compared to untreated cells. Erlotinib did not produce consistent cytotoxic effects and 10 pM doxorubicin produced a sub-maximal effect (90% inhibition; data not shown). PEG-3350, -8000 and -10,000 induced cytotoxicity with potencies of 42.8 (± 5.3), 17.1 (± 0.5) and 7.4 mM (± 1.0), respectively. Maximum effects for PEG-3350, -8000 and - 10.000 were 97, 96 and 96%, respectively. Data are presented as the mean of n=3 (in singlicate) experiments ± standard error of the mean (SEM). IC50 values are quoted as the mean of n=3 experiments, ± SEM.

Figure 5

Figure 5 depicts PEG-induced cytotoxicity in the human HeLa cell-line after 24 hours incubation with (A) PEG-3350, (B) PEG-8000 and (C) PEG-10,000. The effects of the PEG compounds were calculated and plotted as percentage inhibition compared to untreated cells. Erlotinib did not produce consistent cytotoxic effects and 10 μΜ doxorubicin produced a sub-maximal effect (49% inhibition; data not shown). PEG-3350, -8000 and -10,000 induced cytotoxicity with potencies of 29.9 (± 4.2), 11.2 (± 1.7) and 7.0 mM (± 1.1), respectively. Maximum effects for PEG-3350, -8000 and - 10.000 were 96, 97 and 96%, respectively. Data are presented as the mean of n=3 (in triplicate) experiments ± standard error of the mean (SEM). IC50 values are quoted as the mean of n=3 experiments, ± SEM.

Figure 6

Figure 6 depicts PEG-induced cytotoxicity in the human HeLa cell-line after 72 hours incubation with (A) PEG-3350, (B) PEG-8000 and (C) PEG-10,000. The effects of the PEG compounds were calculated and plotted as percentage inhibition compared to untreated cells. Erlotinib did not produce consistent cytotoxic effects and 10 μΜ doxorubicin produced a sub-maximal effect (63% inhibition; data not shown). PEG-3350, -8000 and -10,000 induced cytotoxicity with potencies of 49.6 (± 4.4), 15.6 (± 1.1) and 9.7 mM (± 1.2), respectively. Maximum effects for PEG-3350, -8000 and - 10.000 were 97, 97 and 95%, respectively. Data are presented as the mean of n=3 (in singlicate) experiments ± standard error of the mean (SEM). IC50 values are quoted as the mean of n=3 experiments, ± SEM.

Detailed Description of the Invention.

Compositions of the Invention.

Compositions of the invention may comprise PEG as its sole therapeutically active constituent or may contain one or more therapeutic agents (particularly anti-cancer agents) as described in more detail below. In preferred embodiments, compositions of the present invention are aqueous compositions. Compositions of the present invention, depending, in particular, on the intended preparation (described in more detail below), may be in the form of a solid, semi-solid (e.g. slurry or paste) or liquid.

The term “polyethylene glycol” (PEG), otherwise known as poly(oxyethylene) or polyethylene oxide) (PEO), refers to a polymer of ethylene oxide as well known to those skilled in the art. The polyethylene glycol (PEG) used in the invention typically has the general formula H-(OCH2CH2)n OH. In some other embodiments of the invention as described throughout the specification, other polyethylene glycol compounds may be used such as end-capped structures and polyoxyethylenes that include minor amounts of alkylene oxide units other than ethylene oxide. PEG used in compositions of the invention preferably has a weight average molecular weight (Mw) in a range wherein the lower limit of the range is selected from the group consisting of: 800,1000, 2000, 3000, 4000, 6000 daltons; and an upper limit of the range is, selected independently, from the group consisting of: 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10,000, 12,000, 15,000, 20,000 daltons. Preferred ranges are wherein the lower limit is 3000 or 4000 daltons and the upper limit is, selected independently, 5000, 6000, 7000, 8000, 9000, 10000, 12000 daltons. Some preferred particular ranges have been set forth previously. It will of course be apparent to the skilled reader that the upper limit referred to throughout this specification, although selected independently, is a value higher than that of the lower limit.

For example, the PEG may be PEG 3350, PEG 4000 or PEG 8000 as defined in some national or regional pharmacopeias. Further examples of suitable PEGs recognized in some national or regional pharmacopoeias include Macrogols, for example Macrogol 3350, Macrogol 4000, Macrogol 8000. Macrogol 8000 is particularly preferred. Preferably, the PEG is not systemically absorbed to any significant extent when topically administered to the subject.

Compositions of the present invention comprise PEG at a concentration of 30mg/ml or greater. In preferred embodiments, compositions of the present invention comprise PEG at a concentration in the range of 30mg/ml up to, and including, the maximum solubility available in that composition, e.g. an aqueous solution (for example, at 25°c) for the PEG concerned (having regard, amongst other things, to its Mw). It is recognized that the maximum solubility available for PEG in the composition may be affected by factors such as the prevailing temperature when the composition is prepared, what other constituents (such as described herein) are present in the composition, pH and the like. Such matters are routine considerations for the skilled artisan. In general, it is preferred that compositions of the present invention comprise PEG at a high concentration with respect to the maximum solubility available, i.e. 0.5 fold or greater, 0.6 fold or greater,0.7 fold or greater,0.8 fold or greater, or 0.9 fold or greater of the maximum solubility available for the PEG concerned in that composition (having regard to the matters described herein).

Suitably, compositions of the present invention comprise PEG having a concentration of at least 110mg/ml or greater, at least 120mg/ml or greater, preferably, at least 130mg/ml or greater, e.g. 140mg/ml or greater such as at least 150mg/ml or greater, at least 200mg/ml or greater or 300mg/ml or greater; having regard to the maximum solubility available for the PEG concerned in the composition.

In some embodiments, compositions of the present invention comprise (or consist essentially of) PEG having a concentration in a range wherein the lower limit is 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200mg/ml and the upper limit, selected independently, is 100,110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 300, 350, 400mg/ml, or the upper limit is the maximum solubility available for the PEG concerned, having regard to the matters described herein. For example, compositions of the present invention may comprise PEG at 120 mg/ml to 200 or 300mg/ml, 130mg/ml to 200 or 300 mg/ml, 140 mg/ml to 200 or 300 mg/ml, 150 mg/ml to 200 or 300 mg/ml, 160 mg/ml to 200 or 300 mg/ml, or 160 mg/ml up to, and including the maximum solubility available for the PEG concerned in the composition. Preferred ranges for PEGs having a particular Mw are set forth below.

In some embodiments, compositions of the present invention comprise (or consist essentially of) PEG having a weight average molecular weight (Mw) in a range wherein the lower limit of the range is selected from the group consisting of: 800, 1000, 2000, 3000, 4000, 6000 daltons; and an upper limit of the range is, selected independently, from the group consisting of: 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10,000, 12,000, 15,000, 20,000 daltons. Preferred ranges are wherein the lower limit is 3000 or 4000 daltons and the upper limit is, selected independently, 5000, 6000, 7000, 8000, 9000, 10000, 12000 daltons the composition having a PEG concentration in a range wherein the lower limit is 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200mg/ml and the upper limit, selected independently, is 100, 110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 300, 350, 400mg/ml, or the upper limit is the maximum solubility available for the PEG concerned, having regard to the matters described herein. For example, compositions of the present invention may comprise PEG having a Mw of 3000 to 12,000 daltons, preferably 3000 to 10000 daltons, such as 3350 daltons, 4000 daltons, 8000 daltons or 10000 daltons and a concentration of 120 mg/ml to 200 or 300 mg/ml, 130 mg/ml to 200 or 300mg/ml, 140 mg/ml to 200 or 300 mg/ml, 150 mg/ml to 200 or 300 mg/ml, 160 mg/ml to 200 or 300 mg/ml, or 160 mg/ml up to, and including, the maximum solubility available for the PEG concerned.

Compositions of the present invention may comprise PEG having a Mw of 3350 daltons (“PEG 3350”) at a concentration of 30mg/ml to 670mg/ml. Preferred concentration ranges of PEG 3350 are wherein the lower limit is 30, 40, 50, 60, 70, 80, 90, 100, 120, 150, 200 mg/ml and the upper limit, selected independently, is 150, 200, 250, 300, 400, 500, 600 or 670mg/ml. More preferred ranges are 150mg/ml to 670mg/ml, for example, 167.5mg/ml to 335 mg/ml or 167.5 mg/ml to 670 mg/ml or 335 mg/ml to 670 mgl/ml. Particularly preferred concentrations are 167.5 mg/ml or thereabout, 200 mg/ml or thereabout, 335 mg/ml or thereabout and 670 mg/ml or thereabout. Of these, PEG 3350 at a concentration of 200 mg/ml or thereabout is particularly preferred.

The terms “thereabout” and “about” as referred to in this specification are intended to indicate that strict compliance with the referenced value (to which it is associated) is not necessary. Minor variations of the referenced value, that do not substantially alter the properties conferred, are considered within the ambit of that referenced value.

Compositions of the present invention may comprise PEG having a Mw of 10000 daltons (“PEG 10000”) at a concentration of 30mg/ml to 300mg/ml. Preferred concentration ranges of PEG 10000 are wherein the lower limit is 30, 40, 50, 60, 70, 80, 90, 100, 150mg/ml and the upper limit, selected independently, is 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 300mg/ml. Particularly preferred PEG 10000 ranges are 70 to 400 mg/ml, 100 to 300 mg/ml, 150 to 300 mg/ml. Particularly preferred PEG 10000 concentrations are 75 mg/ml or thereabout, 150 mg/ml or thereabout, and 300 mg/ml or thereabout. Of these, 300 mg/ml is most preferred. PEG 10000, at a concentration of 300 mg/ml or thereabout is a particularly preferred embodiment of the invention.

Compositions of the present invention may comprise PEG having a Mw of 8000 daltons (“PEG 8000”) at a concentration of 30mg/ml to 400 mg/ml. Preferred concentration ranges of PEG 8000 are wherein the lower limit is 30, 40, 50, 60, 70, 80, 90, 100, 150mg/ml and the upper limit, selected independently, is 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390 or 400 mg/ml. Particularly preferred PEG 8000 concentrations are 50, 100, 200 and 400 mg/ml or thereabout. PEG 8000, at a concentration of 200mg/ml or thereabout is also a particularly preferred embodiment of the invention.

Compositions of the present invention may further comprise other constituents such as another therapeutic agent (see below), and one or more excipients. Examples of excipients include one or more electrolytes such as sodium chloride, potassium chloride, sodium bicarbonate, sulphate such as sodium sulphate. In one embodiment, compositions of the invention comprise sodium chloride and potassium chloride and optionally sodium bicarbonate. Compositions of the invention may comprise one or more sweetener(s) (such as aspartame, acesulfame potassium (acesulfame K), sucralose and saccharine and combinations thereof) and one or more flavouring(s) (such as orange, lemon-lime, lemon, citrus, chocolate, tropical fruit, aloe vera, tea, strawberry, grapefruit, blackcurrant, pineapple and vanilla). Compositions may further comprise ascorbate and/or citrate. Compositions of the invention may further comprise preservatives and other additives such as, for example, antimicrobials, anti-oxidants, pharmaceutically acceptable carriers, chelating agents, and inert gases and the like as known and called for by acceptable pharmaceutical practice.

Compositions of the invention may be presented in a variety of preparations. For example, compositions of the invention may be prepared in the form of an aqueous solution or suspension (for example a mouthwash or injectable solution), emulsion, paste (e.g. toothpaste), cream, balm, ointment, foam, paint, sponge, gel, chewing gum, spray, lozenge, troche, syrup (e.g. viscous syrup), linctus, slurry, film (e.g. orodispersible film), tablet (e.g. orodispersible tablet), capsule (e.g. liquid-gel capsule), granule, caplet, buccal patch. Compositions of the present invention may be in the form of an implant. Such implants are known to the skilled artisan, see for example,

Weinberg B.D et al\ Journal of Pharmaceutical Sciences, vol. 97, No. 5, May 2008, 1681-1722. In some embodiments, the implant is made of co-polymers of lactic and glycolic acid. Preferably, the implant is biodegradable following implantation. In some embodiments, the implant is made of co-polymers of lactic and glycolic acid The implant may be configured for sustained and/or slow release of PEG. The implant may be configured to release an effective amount of PEG shortly following implantation, followed by a sustained release of PEG over a period of time. The implant of the invention may be used in conjunction with surgery that resects/ablates at least one EGFR-dependent cancer. In this embodiment, the implant may be placed at the site of resection/ablation to inhibit the development of further EGFR-dependent cancers at the site and in the local region thereof. Particularly preferred preparations of compositions of the invention include solutions (particularly injectable solutions), suspensions, paints.

In some embodiments, compositions of the invention are administered topically to the subject. Topical administration, in the context of the present invention, refers to the application of a composition of the invention to a surface of the subject’s body. Topical administration includes application to an internal surface of the subject. Topical administration includes application to an external surface of the subject, for example, the skin or anus. Compositions of the present invention may be administered to the target area (e.g. the cancer) and in the local region thereof (sometimes referred to herein and in the art as “locoregional administration”). Typically, compositions of the present invention are applied to a region of the cancer that is accessible at the surface of subject’s body. Topical administration may include per os administration of compositions of the invention. For example, topical administration may include swallowing a composition of the invention (particularly for the prevention and/or treatment of CRC). Accordingly, contact between the composition of the invention and the surface exposed region of the cancer (if present) is enabled.

In some embodiments, compositions of the invention may be injected into the target tissue (e.g. the EGFR-dependent cancer) itself and/or in the local region thereof. Accordingly, the present invention further provides a method of treating and/or preventing a EGFR-dependent cancer in a subject, the method comprising injecting an effective amount of the composition of the invention into the target tissue, EGFR-dependent cancer, pre-malignant lesion and/or in the local region thereof, of the subject. Compositions for use in such a method are also provided.

An effective amount of the composition of the invention to be employed therapeutically will depend, for example, on the particular EGFR-dependent cancer to be treated, upon the therapeutic and treatment objectives (e.g. prophylaxis or treatment or both), the route of administration, the age, body mass, condition of the subject undergoing treatment or therapy (for example, by determining the subject’s performance status and/or other co-morbidities ), stage and/or invasiveness (e.g. TNM score) of the cancer (if present), any auxiliary or adjuvant therapies being provided to the subject, and on the subjects previous response (if appropriate) to therapy with compositions of the invention. The duration of therapy with compositions of the invention depends, in part, on the considerations given above. Such considerations are within the purview of the attending physician or healthcare professional.

An effective amount of the composition of the invention may be determined, at least in part, by the desired reduction in EGFR surface expression in the target tissue (for example, the EGFR-dependent cancer). An effective amount of the composition of the present invention may produce in the target tissue a reduction in EGFR expression of at least 30% (or thereabout), for example, at least 40%, compared to the expression observed prior to administration of the composition.

The degree of EGFR reduction may be determined using methods described in the examples herein. In particular, the degree of EGFR reduction may be determined using flow cytometry, as described, for example, in PCT/US2012/035434 or otherwise well known to the skilled artisan.

The EGFR expression status of a target tissue may be determined using standard methods and kits (for example EGFR pharmDx™, available from Dako Denmark A/S, Glostrup, Denmark).

In some embodiments, the composition of the invention is topically administered to the subject so as to coat the target tissue (e.g. the surface exposed region of a EGFR- dependent cancer, and preferably the local tissue region thereof). Compositions of the present invention may be repeatedly administered to the target tissue of the subject to maintain or renew the coating of the target tissue. Thus the present invention provides a method of preventing and/or treating EGFR-dependent cancer in a subject as described in various aspects and embodiments described herein, the method comprises coating the target tissue of the subject with the composition of the invention. In preferred embodiments, the method comprises coating the target tissue so as to produce a PEG concentration at the target tissue/composition interface of greater than 30 mg/ml, preferably greater than 50 mg/ml, more preferably greater than 100 mg/ml such as 150 mg/ml or greater, e.g. 200 mg/ml or greater. Since PEG at the Mw described herein is known to be generally well tolerated, even at relatively high concentrations, with a low risk of serious adverse events, the subject, attending physician or healthcare professional can readily administer an effective amount of the composition of the invention to meet or exceed the PEG concentration at the target tissue/composition interface as set forth herein.

In particularly preferred embodiments, the method comprises coating the target tissue (e.g. surface exposed EGFR-dependent cancer and preferably the local region thereof) with a composition comprising PEG8000 or PEG10000 having a concentration of 150mg/ml to 300mg/ml, preferably 200mg/ml to 300mg/ml. Particular examples of compositions of the invention for this method comprise PEG8000 at a concentration of 200mg/ml or thereabout, or PEG10000 at a concentration of 300mg/ml.

An effective amount of PEG for use in the prophylaxis of a EGFR-dependent cancer may differ from an effective amount of PEG for use in the treatment of EGFR-dependent cancer. In one embodiment, in a prophylaxis setting, a lower amount of PEG is required than typically used in a treatment setting.

Therapeutic agents.

Compositions of present invention may be used in conjunction with one or more therapeutic agents for the prophylaxis and/or treatment of EGFR-dependent cancers. For example, compositions of the invention may be co-administered with the one or more therapeutic agent(s). The term “co-administered” means the coordinated administration of compositions of the invention with one or more therapeutic agents to prevent and/or treat a EGFR-dependent cancer. Such coordinated administration between compositions of the invention and one or more therapeutic agent(s) may be simultaneous, sequential or separate.

Examples of therapeutic agents that may be used in conjunction with compositions of the invention include radiation therapy and anti-cancer agents. The term “anti-cancer agent” means a therapeutic agent that is capable of inhibiting the initiation and/or proliferation of cancer and/or promoting cell death (e.g. by apoptosis) in cancer cells such as those described herein. Such therapeutic agents include those approved by national or regional regulatory authorities for such use.

Examples of anti-cancer agents include agents that target EGFR expression and/or function (for example by inhibiting functional signaling of the EGFR), herein referred to as “anti-EGFR” agents”. Examples of anti-EGFR agents include anti-EGFR antibodies such as cetixumab, panitumumab, zalutumab, nimotuzumab. Other anti-EGFR agents include Erlotinib, Gefitinib, Lapatinib, BIBW-2992.

Examples of anti-cancer agents include agents that target VEGFR expression and/or function (“anti-VEGFR agents”). Examples of anti-VEGFR agents include bevacizumab, sorafenib, sunitinib, vandetanib.

Examples of anti-cancer agents include agents that target IGF-1R expression and/or function (“anti-IGF-lR agents”). Examples of anti-IGF-lR agents include figitumumab and cixtumumab.

Examples of anti-cancer agents include agents that inhibit the mammalian target of rapamycin (“mTOR agents”). Examples of such mTOR agents include Temsirolimus, Everolimus.

Further examples of anti-cancer agents include platinating agents such as cisplatin and carboplatin; taxanes such as paclitaxel and docetaxel; folate anti-metabolites such as pemetrexed; fluorouracil, methotrexate.

Examples of other anti-cancer agents include Dasatinib, Ionafamib and Bortezomib.

In some embodiments, compositions of the present invention comprise the PEG as described herein together (for example in intimate physical admixture) with an effective amount of one or more anti-cancer agents such as described above. Preferably, the PEG is not conjugated to the anti-cancer agent. The reader of this specification may assume that each combination of PEG as described herein together with one or more of the anticancer agents described above is individually and specifically contemplated as an embodiment of the invention.

It will be apparent that an “effective amount” of one or more therapeutic agent(s) need not necessarily be the same weight amount as the “effective amount” of PEG in the composition of the invention. It will also be apparent that when considering the term “effective amount” in relation to radiation therapy, an appropriate dose unit (for example gray (gy) or rad) should be deployed.

In other embodiments of the invention there is provided a kit comprising a composition of the invention together with at least one composition of one or more anti-cancer agents such as described above, optionally together with instructions for use.

Methods of treatment and compositions for use in such methods.

The present invention provides a method for preventing and/or treating a EGFR-dependent cancer (such as any one of the EGFR cancers mentioned above) in a subject comprising (or consisting essentially of) administering an effective amount of the composition of the invention. The present invention also provides compositions for use in the prophylaxis and/or treatment of a EGFR-dependent cancer in a subject.

Compositions of the present invention may be of particular use in treating EGFR-dependent cancers that over-express surface EGFR. The EGFR expression status of a EGFR-dependent cancer in a subject may be determined according to standard methods and kits (for example EGFR pharmDx™, available from Dako Denmark A/S, Glostrup, Denmark).

In one embodiment, the method is for preventing a EGFR-dependent cancer. In another embodiment, the method is for treating a EGFR-dependent cancer. In a further embodiment, the method is for preventing and treating a EGFR-dependent cancer.

The synonymous terms “prophylaxis” and “preventing” and grammatical variations thereof means inhibiting the initiation of a EGFR-dependent cancer and/or inhibiting the progression of a pre-malignant pathology of the epithelium and/or early stage cancer to a later stage cancer.

In some embodiments, prophylaxis methods of the invention are performed prior to a positive diagnosis of a EGFR-dependent cancer.

The term “treat” and grammatical variations thereof means inhibiting the proliferation of a EGFR-dependent cancer and/or promoting cell death in the EGFR-dependent cancer. In some embodiments, treat includes “cure”, although the term cure does not necessarily mean the complete restoration of health with respect to the malignancy. Those skilled in the art recognize that a treatment may have varying degrees of curative effect and as such are encompassed by the term “treat”.

The present invention further provides a method for preventing a EGFR-dependent cancer in a subject in remission of that disease comprising administering to the subject an effective amount of a composition of the invention. The remission may be total or partial. Compositions for use in such a method are also provided.

The present invention further provides a method for treating locally advanced and/or metastatic EGFR-dependent cancer in a subject comprising administering to the subject an effective amount of the composition of the invention.

In another embodiment of the invention there is provided a method for preventing and/or treating a EGFR-dependent cancer (such as any one of the EGFR cancers mentioned above) in a subject susceptible to developing such a cancer comprising administering to the subject an effective amount of the composition of the invention. Such subjects include those with a prior or familial history of (or predisposition to) developing the EGFR-dependent cancer. Such subjects also include those subjects that are frequently exposed to factors known to promote the development of a particular EGFR-dependent cancer. For example, overexposure to ultraviolet radiation (as a result of, for example, sun exposure), is known to promote the occurrence of certain skin cancers. Subjects of this embodiment of the invention may also be afflicted with actinic keratosis which is known to be associated with the development of certain skin cancers.

In another embodiment, there is provided a method for preventing a EGFR-dependent cancer in a subject afflicted with pre-malignant alterations to the epithelium (e.g. actinic keratosis), comprising (or consisting essentially of) administering to the subject an effective amount of a composition of the invention. Pre-malignant alterations may arise as a result of “field cancerization”. Field cancerization refers to a process whereby the epithelium undergoes alterations (which may be multiple and independent of one another) that primes the epithelium for transformation. These alterations may be evident in subtle changes to the epithelium vasculature, cellular dysplasia and other molecular changes to the epithelium. This embodiment may be particularly apt in preventing a EGFR-dependent cancer in subjects with a prior history of (or predisposition to) being afflicted with a EGFR-dependent cancer.

In another aspect of the invention there is provided a method for preventing and/or treating a EGFR-dependent cancer in a subject which method comprises: (a) administering to said subject an effective amount of a therapeutic agent such as radiation therapy and/or an anti-cancer agent, e.g. an anti-EGFR agent (for example an anti-EGFR antibody such as cetixumab); (b) administering to said subject an effective amount of the composition of the invention.

In one embodiment of this aspect of the invention, step (b) and step (a) occur concurrently. In another embodiment step (b) occurs after step (a). In another embodiment, step (b) occurs before step (a). In another embodiment of this aspect of the invention, the method further comprises the step of (c) administering an effective amount of a therapeutic agent e.g. radiation therapy and/or an anti-cancer agent such as an anti-EGFR agent (for example, an anti-EGFR antibody such as cetixumab). In this embodiment, step (b) may occur after step (a) and before step (c). Therefore, an effective amount of the composition of the invention may be administered between cycles of treatment with other therapeutic agents, particularly radiation and/or anticancer agents. The therapeutic agents of step (a) and step (c) need not necessarily be the same. Where the therapeutic agents of step (a) and step (c) are the same, the posology followed in step (a) and step (c) need not necessarily be the same.

In another aspect of the invention, an effective amount of the composition of the invention may be used to treat a EGFR-dependent cancer (such as any one of the EGFR cancers mentioned above) in a subject in conjunction with resection and/or ablation of a EGFR-dependent cancer. Accordingly, there is provided a method for treating a EGFR-dependent cancer in a subject comprising the steps of: (a) resecting and/or ablating at least one EGFR-dependent cancer of the subject; (b) administering an effective amount of the composition of the invention to the subject, preferably to the resected/ablated region of the subject.

Step (a) may occur either before step (b) or after step (b). In some embodiments of this aspect of the invention, there may be a further step (c) comprising the step of administering an effective amount of a therapeutic agent as described herein. Step (c) may occur after step (a) and before, after or concurrently with step (b).

In some embodiments of this aspect of the invention, an effective amount of the composition of the invention may be administered at the site(s) and local region of the surgical resection/ablation e.g. locoregional administration.

The present invention further provides methods for the multi-modal treatment of a EGFR-dependent cancer (that is treatment involving at least two different modalities for treating a EGFR-dependent cancer, e.g. surgery, radiotherapy, chemotherapy) the method comprising administering an effective amount of the composition of the invention.

In accordance with a further aspect of the invention there is provided a method for reducing the tumor burden of a subject afflicted with a EGFR-dependent cancer (such as any one of the EGFR cancers mentioned above) comprising (or consisting essentially of) administering an effective amount of the composition of the invention.

Compositions for use in such as method are also provided. The term “tumor burden” is a term of the art, and refers to the number of cancer cells, the size of a tumor, or the amount of cancer in the body.

In another aspect of the invention there is provided a method of downstaging a EGFR-dependent cancer in a subject afflicted with a EGFR-dependent cancer the method comprising (or consisting essentially of) administering an effective amount of the composition of the invention. Compositions for use in such a method are also provided. The term “downstaging” is a term of the art, and refers to the use of a therapy to reduce the pathological stage of a cancer, and is frequently performed prior to further therapy on the cancer such as surgery. Therefore, this aspect of the invention may also include a further step or steps of: resecting and/or ablating at least one downstaged EGFR-dependent cancer and/or administering an effective amount of a therapeutic agent such as an anti-cancer agent.

The subject referred to in this specification is preferably a mammal and more preferably human.

Exemplification

The following exemplary cell lines (available from the European Collection of Cell Cultures, ECACC, unless otherwise indicated) may be cultured and tested according to the protocol set out below.

Cell Culture

Cells are cultured in DMEM/F-12 media (containing 2.5 mM L-glutamine, 15 mM HEPES, 0.5 mM sodium pyruvate and 1200 mg/L sodium bicarbonate) supplemented with 400 ng/mL of hydrocortisone (Sigma/Aldrich Inc), 10% v/v fetal bovine serum (FBS), and 0.5% v/v Penicillin/Streptomycin (ATCC).

To assess the effect of PEG, these cells are treated with various concentrations of different molecular weights of PEG, or vehicle (phosphate buffered saline (PBS)), for 24 hours. Cells are then assessed for cell proliferation using the WST-1 cell proliferation assay according to the manufacturer’s instructions.

Test Formulations

Three different molecular weights of PEG were used in the current studies: PEG 3,350 (catalogue number: P4338, Sigma-Aldrich) PEG 8,000 (catalogue number: P4463, Sigma-Aldrich) PEG 10,000 (catalogue number: P6667, Sigma-Aldrich)

Effect of various PEGs on proliferation of SK-MEL-2. MKN45 and HeLa cells. SK-MEL-2 cells (HTB-68; American Type Tissue Culture [ATCC], Rockville, MD), a human malignant melanoma cell line, and MKN-45 cells (ACC 409; DSMZ, Braunschweig, Germany), a human gastric adenocarcinoma cell line, were cultured in DMEM medium (Life Technologies, Carlsbad, CA) supplemented with 10% FBS (Life Technologies). HeLa cells (CCL-2; ATCC), a human cervical adenocarcinoma cell line were cultured in RPMI-1640 medium (Life Technologies, Carlsbad, CA) supplemented with 10% FBS (Life Technologies). All cells were cultured at 37°C and 5% C02 in a humidified incubator.

To assess the effect of PEG, cells were seeded in 96-well clear bottom black plates (Coming Life sciences, Tewkesbury, MA) at 5000 cells per well in 100 pL growth medium. Cells were cultured overnight at 37°C, 5% C02 in a humidified incubator.

Cells were incubated with different PEG molecules (PEG-3350, -8000 and -10,000) at concentrations as indicated, erlotinib (Selleckchem, Houston, TX) at 0.5 nM to 10 μΜ, or with 10 pM doxorubicin (Sigma-Aldrich, St. Louis, MO), final volume 125 pL. Cells were then incubated in triplicate for 24 hours or in singlicate for 72 hours.

Healthy cell number was assessed using the alamarBlue reagent (Invitrogen, Carlsbad, CA) and quantification of the metabolic cleavage from non-fluorescent resorufin to the fluorescent resorufin, following manufacturer’s instruction. Briefly, cells were incubated with 12.5 pL alamarBlue reagent (10% [v/v]) for 20 minutes (24 hour treatment) or 60 minutes (72 hour treatment) at 37°C and 5% C02 in a humidified incubator. Fluorescence was determined by excitation at 540 nm and emission at 590 nm using a TECAN infinite M200 instrument (Tecan Group Ltd., Mannedorf, Switzerland).

Concentration-response curves and associated IC50 values were calculated using GraphPad Prism (GraphPad Software, La Jolla, CA).

Results

The results demonstrate potency (IC50) values for_PEG-3350, -8000 and -10,000 in HeLa cells, with potencies of 31.0, 12.1 and 8.1 mM, respectively, after 24 hours incubation (Figure 1). In MKN-45 cells, potencies were 29.9, 11.2 and 7.0 mM, respectively, after 24 hours incubation (Figure 3). Finally, in SK-Mel-2 cells, potencies were 32.9, 12.7 and 5.7 mM, respectively, after 24 hours incubation (Figure 5). PEG-3350, -8000 and -10,000 were all more effective than 10 μΜ doxorubicin and erlotinib in head-to-head comparisons (data not shown) and reduced the proliferating cell number by 86-97%. Furthermore, when the PEG molecules were incubated with each cell-line for longer (72 hours incubation - Figures 2, 4 and 6), the potencies remained broadly similar, but superior efficacy was observed (94-97% inhibition).

Summary/Conclusions:

As discussed above, the goals of the current project were to characterize the antiproliferative effects of PEG against the development of a variety of different cancers, exemplified here by skin, cervical and gastric cancer. The study focus was to define PEG formulations (molecular weights) and concentrations that were maximally effective in causing an anti-proliferative effect in an in vitro cell culture model.

As shown in the results, all PEGs were able to achieve a maximal inhibitory effect of up to 97% within the range of the concentrations studied, and showed markedly superior efficacy to “standard” anti-cancer agents such as doxorubicin and erlotinib (data not shown). The data demonstrated the rank order of molar potency as PEG-10,000 < PEG-8000 < PEG-3350. However, it should be noted that on a gram-for-gram basis the potency of PEG-3350, PEG-8000 or PEG-10,000 were broadly comparable.

We therefore conclude that PEG-3350, PEG-8000 or PEG-10,000 are broadly equi-efficacious, in vitro, in inhibiting proliferation of a variety of cancer cell-lines.

Claims

A composition for use in the prevention and / or treatment of an EGFR-dependent cancer in a subject, wherein the composition comprises polyethylene glycol (PEG) at a concentration of 30 mg / ml or more, wherein the PEG has a weight-average molecular weight (Mw ) of about 800 dalton or more.

The composition of claim 1, wherein the EGFR-dependent cancer is non-squamous cell carcinoma of the head and neck (HNSCC).

The composition of claim 1 or 2, wherein the EGFR-dependent cancer is a squamous cell carcinoma or adenocarcinoma.

A composition according to any one of the preceding claims, wherein the EGFR-dependent cancer is an EGFR cancer selected from the group consisting of: bladder, breast, cervix, colorectum, womb lining, stomach, lung, ovary is gastro-esophagus, pancreas, anus or kidney cancer, non-melanoma skin cancer such as basal cell carcinoma and / or skin squamous cell carcinoma, melanoma cancer of (for example) the skin.

The composition of claim 4, wherein the EGFR-dependent cancer is a colorectal, anus, gastro-esophagus, or a non-melanoma skin cancer.

The composition of claim one of the preceding claims, wherein the PEG has an Mw of from about 800 to about 20,000 daltons, for example from about 2000 daltons to about 15,000 daltons.

The composition of any one of the preceding claims, wherein the PEG has an Mw of from about 3000 daltons to about 12,000 daltons.

The composition of any one of the preceding claims, wherein the PEG has an Mw of from about 3000 daltons to about 10,000 daltons.

The composition of any one of the preceding claims, wherein the PEG has an Mw of from about 3200 daltons to about 9000 daltons.

The composition of any one of the preceding claims, wherein the PEG has an Mw of from about 3000 daltons to about 4000 daltons, about 3500 daltons to about 7000 daltons or about 7000 daltons to about 9000 daltons.

The composition of any one of the preceding claims, wherein the PEG has an Mw of 3350 dalton or thereabouts, 4000 dalton or thereabouts, 8000 dalton or thereabouts, 10000 dalton or thereabouts or 15000 to 20000 dalton.

The composition of claim 11, wherein the PEG has an Mw of 8000 daltons or thereabouts.

The composition of claim 11 or 12, wherein the PEG is a macrogol.

The composition of claim 13, wherein the macrogol is Macrogol 3350 or Macrogol 4000 or Macrogol 8000 or Macrogol 10000 according to the United States Pharmacopeia.

The composition of claim 14, wherein the macrogol is Macrogol 8000 or Macrogol 10000.

A composition according to any one of the preceding claims, comprising PEG in a concentration of 30 mg / ml up to and including the maximum solubility of the PEG in that composition.

A composition according to claim 16, comprising PEG in a concentration of 30 mg / ml to 0.5 times or more, for example 0.6 times or more, 0.7 times or more, 0.8 times or more, 0.9 times or more, or includes the maximum solubility of the PEG in that composition.

The composition of any one of the preceding claims, wherein the PEG has a concentration of at least 110 mg / ml, at least 120 mg / ml, at least 130 mg / ml, at least 140 mg / ml, at least 150 mg / ml has at least 200 mg / ml or at least 300 mg / ml.

The composition of any one of claims 1 to 16, wherein the PEG has a concentration in a region with a lower limit of 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130, 140, 150, 160, 170, 180, 190 or 200 mg / ml and an independently selected upper limit of 100,110, 120, 130, 140, 150, 160, 170, 180, 190, 200, 300, 350 or 400 mg / ml or the maximum solubility of the relevant PEG in the composition as an upper limit.

A composition according to claim 18 or 19, wherein the PEG has a concentration of 120 mg / ml to 200 or 300 mg / ml, 130 mg / ml to 200 or 300 mg / ml, 140 mg / ml to 200 or 300 mg / ml, 150 mg / ml to 200 or 300 mg / ml, 160 mg / ml to 200 or 300 mg / ml or 160 mg / ml up to and including the maximum solubility of the PEG concerned.

A composition for use in the prevention and / or treatment of an EGFR-dependent cancer according to any one of the preceding claims in a person, wherein the composition is polyethylene glycol (PEG) with an Mw or 3350 dalton or thereabouts ("PEG 3350") in a concentration of 30 mg / ml to 670 mg / ml.

The composition of claim 21, wherein the PEG 3350 has a concentration in a region with a lower limit of 30, 40, 50, 60, 70, 80, 90, 100, 120, 150 or 200 mg / ml and an upper limit independently selected therefrom of 150, 200, 250, 300, 400, 500, 600 or 670 mg / ml.

The composition of claim 21 or 22, wherein the PEG 3350 has a concentration of 150 mg / ml to 670 mg / ml, for example, 167.5 mg / ml to 335 mg / ml or 167.5 mg / ml to 670 mg / ml or 335 mg / ml to 670 mg / ml.

The composition of any one of claims 21-23, wherein the PEG 3350 has a concentration selected from 167.5 mg / ml or thereabouts, 200 mg / ml or thereabouts, 335 mg / ml or thereabouts and 670 mg / ml or thereabouts .

The composition of claims 21 to 24, wherein the PEG 3350 has a concentration of 200 mg / ml or thereabouts.

A composition for use in the prevention and / or treatment of an EGFR-dependent cancer according to any of claims 1-20 in a person, wherein the composition is polyethylene glycol (PEG) with an Mw or 10,000 dalton or thereabouts ("PEG 10000" ) in a concentration of 30 mg / ml to 300 mg / ml.

The composition of claim 26, wherein the PEG 10000 has a concentration in region with a lower limit of 30, 40, 50, 60, 70, 80, 90, 100 or 150 mg / ml and an independently selected upper limit of 120, 130, 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280 or 300 mg / ml.

The composition of claim 26 or 27, wherein the PEG 10000 has a concentration of 70 to 400 mg / ml, 100 to 300 mg / ml or 150 to 300 mg / ml.

The composition of any one of claims 26 to 28, wherein the PEG 10000 has a concentration of 75 mg / ml or thereabouts, 150 mg / ml or thereabouts or 300 mg / ml or thereabouts.

The composition of any one of claims 26-29, wherein the PEG 10000 has a concentration of 300 mg / ml or thereabouts.

A composition for use in preventing and / or treating an EGFR-dependent cancer according to any one of claims 1 to 20 in a person, wherein the composition is polyethylene glycol (PEG) with an Mw of 8000 daltons or thereabouts ("PEG 8000" ) in a concentration of 30 mg / ml to 400 mg / ml.

The composition of claim 31, wherein the PEG 8000 has a concentration in a region with a lower limit of 30, 40, 50, 60, 70, 80, 90, 100 or 150 mg / ml and an upper limit of 120, 130 independently selected therefrom. , 140, 150, 160, 170, 180, 190, 200, 220, 240, 260, 280, 300, 310, 320, 330, 340, 350, 360, 370, 380, 390 or 400 mg / ml.

The composition of claim 31 or 32, wherein the PEG 8000 has a concentration of 50 mg / ml or thereabouts, 100 mg / ml or thereabouts, 200 mg / ml or thereabouts or 400 mg / ml or thereabouts.

The composition of 33, wherein the PEG 8000 has a concentration of 200 mg / ml or thereabouts.

A composition according to any one of the preceding claims prepared in the form of an aqueous solution or suspension (e.g. a mouthwash), emulsion, paste (e.g. toothpaste), cream, balm (e.g. lip balm), ointment, foam, paint, sponge, gel, chewing gum, spray, lozenge, pastille, syrup (e.g. viscous syrup), cough drink, dispersion, film (eg mouth-melting film), tablet (eg mouth-melting tablet), capsule ( liquid gel capsule), granule, caplet or mouth patch.

The composition of any one of the preceding claims, wherein PEG is the only therapeutically active ingredient.

The composition of any one of claims 1-35, wherein the composition also comprises a therapeutic agent.

The composition of claim 37, wherein the therapeutic agent is an anti-cancer agent selected from the group consisting of anti-EGFR, anti-VEGFR, anti-IGFR-1R, mTOR agent, platinum agent, a taxane, and a folate anti-metabolite includes.

The composition of claim 37 or 38, wherein the PEG and the therapeutic agent are intimately physically mixed.

The composition of any one of claims 36 to 39, wherein the PEG and the therapeutic agent are not conjugated.

A method for preventing and / or treating an EGFR-dependent cancer in a subject, wherein an effective amount of the composition of any one of the preceding claims is administered.

The method of claim 41, wherein the method is for preventing an EGFR-dependent cancer.

The method of claim 41, wherein the method is for treating an EGFR-dependent cancer.

The method of claim 41, wherein the method is for preventing and treating an EGFR-dependent cancer.

The method of any one of claims 41 to 44, wherein the subject is in remission of an EGFR-dependent cancer.

The method of claim 45, wherein the person is in partial or total remission with respect to the EGFR-dependent cancer.

The method of any one of claims 41 to 46, wherein the subject is susceptible to developing an EGFR-dependent cancer.

The method of claim 46, wherein the person has an earlier case or family history of developing an EGFR-dependent cancer.

A method for preventing and / or treating an EGFR-dependent cancer in a subject, wherein: (a) an effective amount of a therapeutic agent such as a radiotherapeutic agent and / or an anti-cancer agent is administered to the subject; (b) administer to the subject an effective amount of the composition of any one of claims 1-40.

The method of claim 49, wherein step (a) and step (b) are performed simultaneously.

The method of claim 49, wherein step (a) is performed before step (b).

The method of claim 49, wherein step (a) is performed after step (b).

The method of any one of claims 49 to 52, wherein also: (c) an effective amount of a therapeutic agent such as a radiotherapeutic agent and / or an anti-cancer agent is administered to the subject.

54. A method for preventing and / or treating an EGFR-dependent cancer in a subject, wherein: (a) at least one EGFR-dependent cancer and / or a target tissue susceptible to developing an EGFR-dependent cancer takes away and / or cuts away; (b) administer an effective amount of a composition according to any of claims 1-40.

The method of any one of claims 41 to 54, wherein the composition is administered topically.

The method of any one of claims 41 to 55, wherein the composition is administered locoregional to the target tissue.