MUNRO SHONAGH (GB)
WO2014145214A2 | 2014-09-18 | |||
WO2014100719A2 | 2014-06-26 | |||
WO2020217070A1 | 2020-10-29 | |||
WO2018167276A1 | 2018-09-20 | |||
WO2014100719A2 | 2014-06-26 | |||
WO2016178870A1 | 2016-11-10 | |||
WO2017032840A1 | 2017-03-02 | |||
WO2018167269A1 | 2018-09-20 | |||
WO2018167276A1 | 2018-09-20 |
US4727022A | 1988-02-23 | |||
US4659678A | 1987-04-21 | |||
US1901043761A | 1901-01-18 | |||
US4275149A | 1981-06-23 | |||
US4233402A | 1980-11-11 | |||
US4230767A | 1980-10-28 | |||
US4816567A | 1989-03-28 | |||
US5565332A | 1996-10-15 | |||
US5580717A | 1996-12-03 | |||
US5733743A | 1998-03-31 | |||
US0626550A | ||||
GB202108383A | 2021-06-11 |
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Claims: 1. A method of selecting a treatment for a patient with cancer comprising: (i) determining the expression level of biomarker (a) pRb and/or (b) total E2F1 in a cancer cell containing biological sample from the patient; (ii) comparing the expression level(s) in (i) with a reference value for each biomarker, (iii) wherein if the patient’s cancer cells exhibit a decrease in expression of pRb and/or an increase in expression of total E2F1 compared to the reference value the patient is selected for treatment with a PRMT5 inhibitor. 2. The method according to claim, wherein the expression level is expression of protein or nucleic acid. 3. The method of claim 1 or 2, wherein the determination is based on expression level of total E2F1 protein. 4. The method of claim 1 or 2, wherein the determination is based on expression level of pRb protein. 5. The method of claim 1 or 2, wherein the determination is based on expression level of pRb and total E2F1. 6. The method of any one of the preceding claims, wherein the level of protein is detected using an antibody that binds to the protein. 7. The method of claim 6, wherein the antibody is a monoclonal antibody. 8. The method according to any one of claims 1, 2, 4 and 5, wherein reduced expression level of pRb is determined indirectly by identification of a RB1 mutation indicative of reduced or null expression in the cancer cells. 9. A method of selecting a treatment for a patient with cancer comprising determining whether the PRB1 gene in the cancer cells comprises one or more mutations that result in reduced, including null, expression of pRb, wherein if the cancer cells comprise one or more mutations in PRB1 gene that result in reduced expression of pRb the patient is selected for treatment with a PRMT5 inhibitor. 10. The method according to any one of the preceding claims wherein the cancer is selected from selected from the group consisting of: leukaemia, lymphoma, multiple myeloma, lung cancer, liver cancer, breast cancer, head and neck cancer, neuroblastoma, thyroid carcinoma, skin cancer (including melanoma), oral squamous cell carcinoma, urinary bladder cancer, Leydig cell tumour, biliary cancer, such as cholangiocarcinoma or bile duct cancer, brain cancer, pancreatic cancer, colon cancer, colorectal cancer and gynaecological cancers, including ovarian cancer, endometrial cancer, fallopian tube cancer, uterine cancer and cervical cancer, including epithelia cervix carcinoma. In suitable embodiments, the cancer is leukaemia and can be selected from the group consisting of acute lymphoblastic leukaemia, acute myelogenous leukaemia (also known as acute myeloid leukaemia or acute non-lymphocytic leukaemia), acute promyelocytic leukaemia, acute lymphocytic leukaemia, chronic myelogenous leukaemia (also known as chronic myeloid leukaemia, chronic myelocytic leukaemia or chronic granulocytic leukaemia), chronic lymphocytic leukaemia, monoblastic leukaemia and hairy cell leukaemia. In further preferred embodiments, the cancer is acute lymphoblastic leukaemia. In a suitable embodiment the cancer is lymphoma, which may be selected from the group consisting of: Hodgkin’s lymphoma; non-Hodgkin lymphoma; Burkitt’s lymphoma; and small lymphocytic lymphoma. 11. A kit for use in a method of identifying cancer which may be susceptible to treatment by the inhibition of PRMT5, wherein the kit comprises an antibody or antigen-binding portion thereof which specifically binds to E2F-1 protein; and/or an antibody or antigen-binding portion thereof which specifically binds to pRb protein; and/or a nucleic acid oligonucleotide capable of specifically binding to RB1 transcript; and/or a nucleic acid oligonucleotide capable of specifically binding to E2F1 transcript. 12. A kit for use according to claim 11, wherein the kit also comprises assay reagents for detection of antibody target binding or nucleic acid oligonucleotide target binding and/or instructions for use. 13. A PRMT5 inhibitor for use in treating a cancer whose cells express greater than normal levels of total E2F1 protein and/or reduced levels of pRb protein compared to normal. 14. The PRMT5 inhibitor for use according to claim 13, wherein the cancer cells express greater than normal levels of total E2F1 protein. 15. The PRMT5 inhibitor for use according to claim 13 or 14, wherein the cancer cells express reduced levels of pRb protein compared to normal. 16. The PRMT5 inhibitor for use according to any one of claims 13 to 15, wherein the cancer cells express greater than normal levels of total E2F1 protein and reduced levels of pRb protein compared to normal. 17. A PRMT5 inhibitor for use in treating a pRb defective cancer or for use in treating a cancer whose cells express reduced levels of pRb protein compared to normal. 18. The PRMT5 inhibitor for use according to any one of claim 13 to 17, selected from the group consisting of: an antibody, RNA interference molecule, antisense oligonucleotide or a small molecule compound. 19. The PRMT5 inhibitor for use according to claim 14, wherein the small molecule compound PRMT5 inhibitor is selected from: GSK3326595 (pemrametostat), PF-6939999, JNJ-64619178 (onametostat) and LLY-283. 20. The PRMT5 inhibitor for use according to any one of the claims 13 – 19, wherein the cancer is selected from the group consisting of: selected from the group consisting of: leukaemia, lymphoma, multiple myeloma, lung cancer, liver cancer, breast cancer, head and neck cancer, neuroblastoma, thyroid carcinoma, skin cancer (including melanoma), oral squamous cell carcinoma, urinary bladder cancer, Leydig cell tumour, biliary cancer, such as cholangiocarcinoma or bile duct cancer, brain cancer, pancreatic cancer, colon cancer, colorectal cancer and gynaecological cancers, including ovarian cancer, endometrial cancer, fallopian tube cancer, uterine cancer and cervical cancer, including epithelia cervix carcinoma. In suitable embodiments, the cancer is leukaemia and can be selected from the group consisting of acute lymphoblastic leukaemia, acute myelogenous leukaemia (also known as acute myeloid leukaemia or acute non-lymphocytic leukaemia), acute promyelocytic leukaemia, acute lymphocytic leukaemia, chronic myelogenous leukaemia (also known as chronic myeloid leukaemia, chronic myelocytic leukaemia or chronic granulocytic leukaemia), chronic lymphocytic leukaemia, monoblastic leukaemia and hairy cell leukaemia. In further preferred embodiments, the cancer is acute lymphoblastic leukaemia. In a suitable embodiment the cancer is lymphoma, which may be selected from the group consisting of: Hodgkin’s lymphoma; non- Hodgkin lymphoma; Burkitt’s lymphoma; and small lymphocytic lymphoma. 21. The PRMT5 inhibitor for use according to claim 17, wherein the cancer is selected from: breast cancer, esophageal cancer, bladder cancer, lung cancer, hematopoietic cancer, lymphoma, medulloblastoma, rectum adenocarcinoma, colon adenocarcinoma, gastric cancer, pancreatic cancer, liver cancer, adenoid cystic carcinoma, lung adenocarcinoma, head and neck squamous cell carcinoma, brain tumors, hepatocellular carcinoma, renal cell carcinoma, melanoma, oligodendroglioma, ovarian clear cell carcinoma, and ovarian serous. |
Compound 208 in WO 2014/100719 (Epizyme) is GSK3326595 (pemrametostat). The compound of Example 2 in WO 2016/178870 (Eli Lilly) is LLY-283 Compound 80 in WO 2017/032840 (Janssen Pharmaceuticals) is JNJ-64619178. See also Fereira de Freitas et al., (Molecules.24:4492, 2019). Other suitable PRMT5 inhibitors include: (1) WO 2018/167269 (Argonaut Therapeutics Limited) which disclose compounds of formula I, or a salt, solvate or hydrate thereof, wherein, R1, R3, R4, R5 and R6 are each independently selected from hydrogen and C1-3 alkyl; R2 is selected from hydrogen and R14; X is O or NR9, where R9 is hydrogen or a C1-3 alkyl; Y1 is a group selected from one of formula A and B, where each R’” is independently selected from H and C1-3 alkyl; Q is C or N; T is selected from a fused phenyl group and a fused 5- or 6-membered heteroaryl group, wherein each group is optionally substituted with one or more substituents selected from halo and C1-3 alkyl; and R7 and R8 are taken together with the intervening nitrogen atom to form a 3-12 membered heterocycloalkyl ring, wherein the 3-12 membered heterocycloalkyl ring is optionally substituted with one or more R10; and/or optionally fused to one or more C6-12 aryl, C5-12 heteroaryl, C3-8 cycloalkyl and 3-12 membered heterocycloalkyl rings, wherein each fused C6-12 aryl, C5-12 heteroaryl, C3-8 cycloalkyl and 3-12 membered heterocycloalkyl ring is optionally substituted with one or more R14; R10 is selected from a group of the formula L1-L2-R11 or L2-L1-R11, where L1 is a linker of the formula –[CR12R13]n-, where n is an integer of from 0 to 3 and R12 and R13 are in each instance each independently selected from H and C1 to C2 alkyl, where L2 is absent or a linker that is selected from O, S, SO, SO2, N(R’), C(O), C(O)O, [O(CH2)r]s, [(CH2)rO]s, OC(O), CH(OR’), C(O)N(R’), N(R’)C(O), N(R’)C(O)N(R’), SO2N(R’) or N(R’)SO2, where R’ and R” are each independently selected from hydrogen and a C1 to C2 alkyl, and where r is 1 or 2 and s is 1 to 4, R11 is independently selected from hydrogen, CN, NO2, hydroxyl, =O, halogen, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, C6-12 aryl, C5-12 heteroaryl, 3-10 membered heterocycloalkyl, –C(=O)R d , –C(=O)OR d , –C(=O)NR e R d , –C(O)C(=O)R d , –NR e R d , –NR e C(=O)R d , –NR e C(=O)OR d , –NR e C(=O)NR e R d , – NR e S(=O)2R d , –NR e S(=O)2NR e R d , –OR d , –SR d , –OC(=O)R d , –OC(=O)NR e R d , – OC(=O)OR d , –S(=O)2R d , –S(=O)R d , –OS(=O)R d , –OS(=O)2R d , –OS(=O)2OR d , – S(=O)NR e R d , –OS(=O)2NR e R d , and –S(=O)2NR e R d , wherein, where R11 is independently selected from C3-6 cycloalkyl, C6-12 aryl, C5-12 heteroaryl and 3-10 membered heterocycloalkyl, each C3-6 cycloalkyl, C6-12 aryl, C5-12 heteroaryl and 3-10 membered heterocycloalkyl is optionally substituted with one or more R14; each R a and R b is independently selected from hydrogen and C1-6 alkyl; each R d is independently selected from hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, 3-7 membered heterocycloalkyl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl and C6-11 aryl, wherein said C1-6 alkyl, C6-11 aryl, 3-7 membered heterocycloalkyl and C3-6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, =O, halogen, CN, COR a , NR a R b , C1-6 haloalkyl, C3-6 cycloalkyl, C6-11 aryl, 3-7 membered heterocycloalkyl, C1-6 alkyl and O-C1-6 alkyl; each R e is independently selected from hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl; or R e and R d , when attached to the same atom, together with the atom to which they are attached form a 3-7 membered heterocycloalkyl ring, optionally substituted with one or more substituent selected from hydroxyl, =O, halogen, CN, COR a , NR a R b , C1-6 haloalkyl, C3-6 cycloalkyl, C6-11 aryl, 3-7 membered heterocycloalkyl, C1-6 alkyl and O-C1-6 alkyl; and R 14 is independently selected from halo, CN, NO2, hydroxyl, =O, halogen, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, C6-12 aryl, 5-6 membered heteroaryl, 3-7 membered heterocycloalkyl, C1-6alkylC6-12aryl, –C(=O)R d , –C(=O)OR d , –C(=O)NR e R d , –C(O)C(=O)R d , –NR e R d , –NR e C(=O)R d , –NR e C(=O)OR d , –NR e C(=O)NR e R d , –NR e S(=O)2R d , –NR e S(=O)2NR e R d , –OR d , –SR d , –OC(=O)R d , – OC(=O)NR e R d , –OC(=O)OR d , –S(=O)2R d , –S(=O)R d , –OS(=O)R d , –OS(=O)2R d , – OS(=O)2OR d , –S(=O)NR e R d , –OS(=O)2NR e R d , and –S(=O)2NR e R d . (2) WO 2018/167276 (Argonaut Therapeutics Limited) which disclose compounds of formula I, or a salt, solvate or hydrate thereof,
wherein, Y 1 is a group selected from one of formula A and B, ; X is selected from O, S, CH and NR 7 ; X 1 is selected from C and N; Y is selected from a fused aryl group and a fused heteroaryl group, where each group is optionally substituted with one or more R 11 ; n is 1 and L is selected from –(CH2)pN(R a )C(O)–, –(CH2)pC(O)N(R a )–, – (CH2)pN(R a )S(Oq)–, –(CH2)pS(Oq)N(R a )–, –(CH2)pN(R b )C(O)N(R b )–, – (CH2)pN(R c )C(O)O–, and –(CH2)pOC(O)N(R c )–; or n is 0 and L is selected from R d (R e )NC(O)–, –R d (R e )NC(O)N(R b )–, R d (R e )NC(O)O–, R d (R e )NS(Oq) and R d (R e )N–; p is a number selected from 0, 1, 2 and 3; q is a number selected from 1 and 2; Z is selected from C6-11aryl optionally substituted by one or more R 10 , (C7- 16)alkylaryl optionally substituted by one or more R 10 , C3-11cycloalkyl optionally substituted by one or more R 10 , (C4-17)cycloalkylalkyl optionally substituted by one or more R 10 , 3-15 membered heterocycloalkyl optionally substituted by one or more R 10 , 4-21 membered alkylheterocycloalkyl optionally substituted by one or more R 10 , 5-15 membered heteroaryl optionally substituted by one or more R 10 , and 6-21 membered alkylheteroaryl optionally substituted by one or more R 10 ; R 1 is selected from hydrogen, halogen, –NR e R d , OR f , and C1-6 alkyl optionally substituted with one or more R 9 ; R 2 is selected from hydrogen, halogen and C1-6 alkyl optionally substituted with one or more R 9 ; R 3 , R 4 , R 5 and R 6 are independently selected from hydrogen, halogen and C1-6 alkyl optionally substituted with one or more R 9 ; R 7 is selected from hydrogen, hydroxyl, C1-6 alkyl, C1-6 haloalkyl, phenyl and C3- 6 cycloalkyl, wherein said C1-6 alkyl, phenyl and C3-6 cycloalkyl are optionally substituted by one or more substituents selected from hydroxyl, halogen, =O, CN, COR a , NR a R b , C1-6 haloalkyl, C3-6 cycloalkyl, C6-11 aryl, 3-7 membered heterocycloalkyl, C1-6 alkyl and O-C1-6 alkyl; each R 9 is independently selected from hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, 3-7 membered heterocycloalkyl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl and phenyl, wherein said C1-6 alkyl, phenyl, 3-7 membered heterocycloalkyl and C3-6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, =O, halogen, CN, NR a R b , COR a , C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 3-7 membered heterocycloalkyl, C1-6 alkyl and O-C1-6 alkyl; each R 10 is independently selected from hydrogen, hydroxyl, =O, halogen, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C1-6 alkyl, O-C1-6 alkyl, C3-6 cycloalkyl, phenyl, 5-6 membered heteroaryl, 3-7 membered heterocycloalkyl, –C(=O)R d , –C(=O)OR d , – C(=O)NR e R d , –C(O)C(=O)R d , –NR e R d , –NR e C(=O)R d , –NR e C(=O)OR d , – NR e C(=O)NR e R d , –NR e S(=O)2R d , –NR e S(=O)2NR e R d , –OR d , –SR d , –OC(=O)R d , – OC(=O)NR e R d , –OC(=O)OR d , –S(=O)2R d , –S(=O)R d , –OS(=O)R d , –OS(=O)2R d , – OS(=O)2OR d , –S(=O)NR e R d , –OS(=O)2NR e R d , and –S(=O)2NR e R d , where said C3-6 cycloalkyl, C1-6 alkyl, phenyl, 5-6 membered heteroaryl and 3-7 membered heterocycloalkyl are optionally substituted with one or more groups selected from hydroxyl, halogen, =O, CN, C1-6 haloalkyl, C1-6 haloalkoxy, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl; R 11 is selected from hydrogen, hydroxyl, halogen, CN, NR a R b , C1-6 haloalkyl, 3- 7 membered heterocycloalkyl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl and phenyl, wherein said C1-6 alkyl, phenyl, 3-7 membered heterocycloalkyl and C3-6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, =O, halogen, CN, COR a , NR a R b , C1-6 haloalkyl, C3-6 cycloalkyl, C6-11 aryl, 3-7 membered heterocycloalkyl, C1-6 alkyl and O-C1-6 alkyl; each R a , R b and R c is independently selected from hydrogen and C1-6alkyl; each R d is independently selected from hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, 3-7 membered heterocycloalkyl, C3-6 cycloalkyl, C1-6 alkyl, O-C1-6 alkyl and C6-11 aryl, wherein said C1-6 alkyl, C6-11 aryl, 3-7 membered heterocycloalkyl and C3-6 cycloalkyl are optionally substituted with one or more groups selected from hydroxyl, =O, halogen, CN, COR a , NR a R b , C1-6 haloalkyl, C3-6 cycloalkyl, C6-11 aryl, 3-7 membered heterocycloalkyl, C1-6 alkyl and O-C1-6 alkyl; each R e is independently selected from hydrogen, hydroxyl, halogen, CN, C1-6 haloalkyl, C3-6 cycloalkyl, C1-6 alkyl and O-C1-6 alkyl; or R e and R d , when attached to the same atom, together with the atom to which they are attached form a 3-7 membered heterocycloalkyl ring, optionally substituted with one or more substituent selected from hydroxyl, =O, halogen, CN, COR a , NR a R b , C1-6 haloalkyl, C3-6 cycloalkyl, C6-11 aryl, 3-7 membered heterocycloalkyl, C1-6 alkyl and O-C1-6 alkyl; and R f is independently selected from hydrogen and C1-6 alkyl optionally substituted with one or more substituents selected from hydroxyl, halogen, CN, COR a , NR a R b , C1-6 haloalkyl, C3-6 cycloalkyl, phenyl, 3-7 membered heterocycloalkyl and O-C1-6 alkyl. (3) GB2108383.7 (Argonaut Therapeutics Limited) which discloses compounds of formula (1) or a deuterated form, salt, solvate, or hydrate thereof, (1) wherein: R 1A is represented by formula (A1), (A1) Z is =O; T taken together with the intervening carbon and nitrogen atoms (e.g. shown in formula (A1)) is selected from a monocyclic 5- to 7-membered heterocycloalkyl group, a fused bicyclic 6- to 10-membered heterocycloalkyl group and a bridged bicyclic 6- to 9-membered heterocycloalkyl group, wherein each of the monocyclic 5- to 7- membered heterocycloalkyl group, the fused bicyclic 6- to 10-membered heterocycloalkyl group and the bridged bicyclic 6- to 9-membered heterocycloalkyl group is optionally substituted with one or more R S1 ; R S1 is selected from C1-6alkyl, C2-6alkenyl, C2-6alkynyl, C1-6alkoxy, C3-12cycloalkyl, hydroxy, halo, CN and nitro, wherein the C1-6alkyl, the C2-6alkenyl, the C2-6alkynyl and the C3-12cycloalkyl is each optionally substituted with one or more R S2 ; and R S2 is selected from hydroxy, halo, CN and nitro. Any of these PRMT5 compounds can be used in the present invention. In particular embodiments, the PRMT5 inhibitor for use in the present invention is a small molecule compound selected from the group consisting of: GSK3326595 (pemrametostat), PF-6939999, JVNJ-64619178 (onametostat), LLY-283 and PRT543. The PRMT5 inhibitor for use in the fourth or fifth aspects of the invention may be formulated as a pharmaceutical composition. The pharmaceutical composition may comprise at least one pharmaceutically-acceptable excipient. The dosage, route of administration and indeed treatment regime can be determined by the person of sill in the art. The term “pharmaceutically-acceptable excipient” as used herein means one or more compatible solid or liquid fillers, diluents or encapsulating substances that are suitable for administration into a human. The term “excipient” denotes an organic or inorganic ingredient, natural or synthetic, with which the active ingredient is combined to facilitate the application. Types of suitable excipient are salts, buffering agents, wetting agents, emulsifiers, preservatives, compatible carriers, diluents, carriers, vehicles, supplementary immune potentiating agents such as adjuvants and cytokines that are well known in the art and are available from commercial sources for use in pharmaceutical preparations (see, e.g. Remington: The Science and Practice of Pharmacy with Facts and Comparisons: Drugfacts Plus, 20th Ed. Mack Publishing; Kibbe et al., (2000) Handbook of Pharmaceutical Excipients, 3rd Ed., Pharmaceutical Press; and Ansel et al., (2004) Pharmaceutical Dosage Forms and Drug Delivery Systems, 7th Ed., Lippencott Williams and Wilkins). Optionally, the pharmaceutical compositions contain one or more other therapeutic agents or compounds. Suitable pharmaceutically acceptable excipients are relatively inert and can facilitate, for example, stabilisation, administration, processing or delivery of the active compound/agent into preparations that are optimised for delivery to the body, and preferably directly to the site of action. The pharmaceutical compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use. When administered, the PRMT5 inhibitor is administered in pharmaceutically acceptable preparations/compositions. Administration may be enteral (e.g. oral), i.e., substance is given via the gastrointestinal tract, or parenteral, i.e., substance is given by other routes than the digestive tract such as by injection. Large biologic molecules or nucleic acid molecules (such as certain vaccines) are typically administered parenterally by injection. Pharmaceutical compositions for parenteral administration (e.g. by injection), include aqueous or non-aqueous, isotonic, pyrogen-free, sterile liquids (e.g. solutions, suspensions), in which the active ingredient/agent is dissolved, suspended, or otherwise provided (e.g. in a liposome or other microparticulate). Such liquids may additionally contain one or more pharmaceutically acceptable carriers, such as anti- oxidants, buffers, stabilisers, preservatives, suspending agents, and solutes that render the formulation isotonic with the blood (or other relevant bodily fluid) of the intended patient. In particular embodiments, the composition may be lyophilised to provide a powdered form that is ready for reconstitution as and when needed. When reconstituted from lyophilised powder the aqueous liquid may be further diluted prior to administration. For example, diluted into an infusion bag containing 0.9% sodium chloride injection, USP, or equivalent, to achieve the desired dose for administration. In particular embodiments, such administration can be via intravenous infusion using an intravenous (IV) apparatus. Suitably, the PRMT5 inhibitor agent is formulated in accordance with routine procedures as pharmaceutical compositions adapted for intravenous administration to human beings. Typically, the active agent for IV administration is in solution, e.g. in sterile isotonic aqueous buffer. Where necessary, the compositions can also include a solubilizing agent. Compositions for IV administration can optionally include a local anaesthetic such as lignocaine to ease pain at the site of the injection. Generally, the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule. Where the PRMT5 inhibitor agent is to be administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline. Where the PRMT5 inhibitor agent is administered by injection, an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration. Compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example, prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pre-gelatinised maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium hydrogen phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets can be coated by methods well known in the art. Liquid preparations for oral administration can take the form of, for example, solutions, syrups or suspensions, or they can be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations can be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, cellulose derivatives or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters, ethyl alcohol or fractionated vegetable oils); and preservatives (e.g., methyl or propyl-p- hydroxybenzoates or sorbic acid). The preparations can also contain buffer salts, flavouring, colouring and sweetening agents as appropriate. Oral compositions can include standard vehicles such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like. Compositions for use in accordance with the present invention can be formulated in conventional manner using one or more physiologically acceptable excipients. Thus, the PRMT5 inhibitor agent and optionally another therapeutic or prophylactic agent and their physiologically acceptable salts and solvates can be formulated into pharmaceutical compositions for administration by inhalation or insufflation (either through the mouth or the nose) or oral, parenteral or mucosal (such as buccal, vaginal, rectal, sublingual) administration. In a particular embodiment, local or systemic parenteral administration is used. The pharmaceutical compositions for use the treatment methods of the invention are for administration in an effective amount. An “effective amount” is the amount of a composition that alone, or together with further doses, produces the desired response. Suitably, the PRMT5 inhibitor agent can be administered as a pharmaceutical composition in which the pharmaceutical composition comprises between 0.1-1mg, 1-10 mg, 10-50mg, 50-100mg, 100-500mg, or 500mg to 5g of the PRMT5 inhibitor agent. The preparation of a suitable pharmaceutical composition of the drug and the dosage to administer to a subject is within the capabilities of a person of skill in the art. Cancers The various aspects of the invention that use cancer cells, or are directed to methods or uses for treating cancer, apply to any cancer. Suitably, the cancer is selected from the group consisting of: leukaemia, lymphoma, multiple myeloma, lung cancer, liver cancer, breast cancer, head and neck cancer, neuroblastoma, thyroid carcinoma, skin cancer (including melanoma), oral squamous cell carcinoma, urinary bladder cancer, Leydig cell tumour, biliary cancer, such as cholangiocarcinoma or bile duct cancer, brain cancer, pancreatic cancer, colon cancer, colorectal cancer and gynaecological cancers, including ovarian cancer, endometrial cancer, fallopian tube cancer, uterine cancer and cervical cancer, including epithelia cervix carcinoma. In suitable embodiments, the cancer is leukaemia and can be selected from the group consisting of acute lymphoblastic leukaemia, acute myelogenous leukaemia (also known as acute myeloid leukaemia or acute non-lymphocytic leukaemia), acute promyelocytic leukaemia, acute lymphocytic leukaemia, chronic myelogenous leukaemia (also known as chronic myeloid leukaemia, chronic myelocytic leukaemia or chronic granulocytic leukaemia), chronic lymphocytic leukaemia, monoblastic leukaemia and hairy cell leukaemia. In further preferred embodiments, the cancer is acute lymphoblastic leukaemia. In a suitable embodiment the cancer is lymphoma, which may be selected from the group consisting of: Hodgkin’s lymphoma; non- Hodgkin lymphoma; Burkitt’s lymphoma; and small lymphocytic lymphoma. In particular embodiments the cancer is selected from: breast cancer, esophageal cancer, bladder cancer, lung cancer, hematopoietic cancer, lymphoma, medulloblastoma, rectum adenocarcinoma, colon adenocarcinoma, gastric cancer, pancreatic cancer, liver cancer, adenoid cystic carcinoma, lung adenocarcinoma, head and neck squamous cell carcinoma, brain tumors, hepatocellular carcinoma, renal cell carcinoma, melanoma, oligodendroglioma, ovarian clear cell carcinoma, and ovarian serous. In particular embodiments, the methods and uses disclosed herein provide a precision medicine approach, such as one that targets a particular type of tumour, or sub-set of patients with a particular tumour, or particular stage of tumour, or even an individual patient. Suitably the methods of the first or second aspects of the invention serve to identify the cancer patient(s) most suited for treatment with a PRMT5 inhibitor. Suitably the treatment of such cancers may achieve effective treatment of the cancer by preventing or treating the development of the cancer, by preventing or treating the progression of the cancer, by preventing or treating the recurrence of the cancer, or by preventing or treating the propagation (including metastasis) of the cancer. Computer-implemented methods According to a sixth aspect of the invention there is provided a computer- implemented method to aid in selecting a treatment for a patient with cancer, comprising the steps of: (iv) receiving a value for the level of biomarker (a) pRb and/or (b) total E2F1 in a cancer cell containing biological sample from the patient; (v) comparing the level(s) in (i) with a reference value for each biomarker, (vi) wherein if the patient’s cancer cells exhibit a decrease in level of pRb and/or an increase in level of total E2F1 compared to the reference value the patient is selected for treatment with a PRMT5 inhibitor. Suitably, the level is expression level. The term “computer-implemented” as used herein means that the method is carried out in an automated fashion on a data processing unit which is, typically, comprised in a computer or similar data processing device. The data processing unit shall receive values for the level of the biomarkers (i.e. pRb and/or (b) total E2F1). Such values can be the amounts, relative amounts or any other calculated value reflecting the amount as described elsewhere herein in detail. Accordingly, it is to be understood that the aforementioned method does not require the determination of amounts for the biomarkers but rather uses values for already predetermined amounts. The present invention also, in principle, contemplates a computer program, computer program product or computer readable storage medium having tangibly embedded said computer program, wherein the computer program comprises instructions which, when run on a data processing device or computer, carry out the method of the present invention as specified above. Specifically, the present disclosure further encompasses: - a computer or computer network comprising at least one processor, wherein the processor is adapted to perform the method according to one of the aspects described in this description, - a computer loadable data structure that is adapted to perform the method according to one of the aspects described in this description while the data structure is being executed on a computer, - a computer script, wherein the computer program is adapted to perform the method according to one of the aspects described in this description while the program is being executed on a computer, - a computer program comprising program means for performing the method according to one of the aspects described in this description while the computer program is being executed on a computer or on a computer network, - a computer program comprising program means according to the preceding embodiment, wherein the program means are stored on a storage medium readable to a computer, - a storage medium, wherein a data structure is stored on the storage medium and wherein the data structure is adapted to perform the method according to one of the aspects described in this description after having been loaded into a main and/or working storage of a computer or of a computer network, - a computer program product having program code means, wherein the program code means can be stored or are stored on a storage medium, for performing the method according to one of the aspects described in this description, if the program code means are executed on a computer or on a computer network, - a data stream signal, typically encrypted, comprising a data for parameters as defined herein elsewhere, and - a data stream signal, typically encrypted, comprising the assessment provided by the methods of the present invention. Kit The present invention also includes kits, e.g., comprising one or more tools capable of quantifying the amount of pRb and/or E2F1 biomarkers in a sample. According to a third aspect of the invention there is provided a kit for use in the method of the first aspect of the invention, which kit comprises one or more reagents capable of determining the expression level of pRb and/or total E2F1. Suitably, the kit comprises an antibody or antigen-binding portion thereof which specifically binds to E2F-1 protein; and/or an antibody or antigen-binding portion thereof which specifically binds to pRb protein; and/or a nucleic acid oligonucleotide capable of specifically binding to RB1 transcript; and/or a nucleic acid oligonucleotide capable of specifically binding to E2F1 transcript. In particular embodiments, the oligonucleotide capable of specifically binding to one of the biomarker transcripts is a primer or a probe. Optionally, the primer or probe is labelled, such as with a fluorescent or radioactive label. Typically, the kit will contain an antibody or antigen-binding moiety that is capable of binding to the biomarker in protein form (e.g. E2F1 protein or pRb protein) and/or a primer or probe capable of binding the biomarker in nucleic acid form (e.g. E2F1 transcript or RB1 transcript). Optionally such antibody or antigen-binding moiety, primer or probe may be labelled, such as fluorescently. The kit may also include instructions for use and may also contain additional elements needed to practice the method described on the instructions in the kit. The kit may also include information on interpreting the data and making a call, e.g. the threshold levels for interpreting whether the levels of the biomarker signify that the patient is likely to respond favourably to a PRMT5 inhibitor. The kit comprises an antibody as described here, or epitope-binding fragment thereof. The kit may also comprise means for obtaining a biological sample, such as a spatula or a dipstick or a container for accepting the sample. The kit may also comprise one or more assay components for detecting the amount of total E2F-1 or pRb protein. Preferably the assay comprises an immunoassay, such as an ELISA. The kit may also comprise one or more assay components for detecting the amount of E2F-1 or RB1 transcript. Preferably the assay is RT-PCR. In particular embodiments, the kit also comprises a positive control and/or a negative control. These process controls act as quality control to ensure valid assay results. The presence and/or amount of total E2F-1 or pRB proteins in a sample may be determined by standard immunochemical techniques which are well known to the skilled person (for example immunohistochemistry, radioimmunoassay, ELISA, Western blot, fluorescence assay, DELFIA®, LANCE, FRET, etc). The method may preferably be carried out as a high throughput screen. The presence and/or amount of E2F-1 or RB1 transcript in a sample may be determined by standard nucleic acid quantitation techniques which are well known to the skilled person (for example RT-PCR, qPCR). An increase in the total E2F-1 protein or E2F-1 encoding transcript in a patient’s cancer cell sample compared to a reference value, such as levels in a normal cell sample or normal reference value, indicates that the patient is suitable for treatment with a PRMT-5 inhibitor. A decrease in the amount of pRb protein or RB1 transcript in a patient’s cancer cell sample compared to the reference value (e.g. a normal cell sample or normal reference value) indicates that the patient is suitable for treatment with a PRMT-5 inhibitor. Further aspects and embodiments will be apparent to those skilled in the art. All documents mentioned in this text are incorporated herein by reference. Aspects and embodiments of the present invention will now be discussed with reference to the following Examples and accompanying Figures. Description of Figures Figure1. PRMT5 inhibition mediates cancer cell death and this effect is E2F1 dependent. U2OS cells were transfected with PRMT5 (P5), E2F-1 (E2F1) or control (NC) or siRNA as indicated, and colony growth measured at 10 days after staining with crystal violet. (a) Levels of E2F1 and PRMT5 in siRNA treated cell is shown by western blot (b). Figure 2. Cells with genetic deletion of E2F1 are less sensitive to PRMT5 inhibition. (a) Cell viability assay in T-47D cell line (breast cancer) (b) Cell viability assay in HCT116 cell line (colorectal cancer). Figure 3. Cells with genetic deletion of pRb are more sensitive to PRMT5 inhibition. (a) Cell viability assay in T-47D cell line (breast cancer) (b) Cell viability assay in U2OS cell line (bone cancer). Figure 4. Cells with genetic deletion of E2F1 are less sensitive to PRMT5 inhibitor GSK3326595. (a) Cell viability assay in HCT116 cell line (colorectal cancer) (b) Cell viability assay in T-47D cell line (breast cancer). Figure 5. Cells with genetic deletion of E2F1 are less sensitive to PRMT5 inhibitor PF06939999. (a) Cell viability assay in HCT116 cell line (colorectal cancer) (b) Cell viability assay in T-47D cell line (breast cancer). Figure 6. Cell viability assay in HCT116 cell line (colorectal cancer). Cells with genetic deletion of E2F1 are less sensitive to PRMT5 inhibitor JNJ64619178. Figure 7. Cell viability assay in HCT116 cell line (colorectal cancer). Cells with genetic deletion of E2F1 are less sensitive to PRMT5 inhibitor LLY283. Figure 8. Cell viability assay in T-47D cell line (breast cancer). Cells with genetic deletion of pRb are more sensitive to PRMT5 inhibitor GSK3326595. Figure 9. Cell viability assay in T-47D cell line (breast cancer). Cells with genetic deletion of pRb are more sensitive to PRMT5 inhibitor PF06939999. Sequences: SEQ ID NO: 1 Gene Name: RB1 (RB transcriptional corepressor 1) Gene ID: 5925 Protein ID: NP_000312.2 CCDS: CCDS31973.1 RB1 Nucleotide Sequence (2787 nt): ATGCCGCCCAAAACCCCCCGAAAAACGGCCGCCACCGCCGCCGCTGCCGCCG CGGAACCCCCGGCACCGCCGCCGCCGCCCCCTCCTGAGGAGGACCCAGAGC AGGACAGCGGCCCGGAGGACCTGCCTCTCGTCAGGCTTGAGTTTGAAGAAACA GAAGAACCTGATTTTACTGCATTATGTCAGAAATTAAAGATACCAGATCATGTCA GAGAGAGAGCTTGGTTAACTTGGGAGAAAGTTTCATCTGTGGATGGAGTATTGG GAGGTTATATTCAAAAGAAAAAGGAACTGTGGGGAATCTGTATCTTTATTGCAG CAGTTGACCTAGATGAGATGTCGTTCACTTTTACTGAGCTACAGAAAAACATAG AAATCAGTGTCCATAAATTCTTTAACTTACTAAAAGAAATTGATACCAGTACCAAA GTTGATAATGCTATGTCAAGACTGTTGAAGAAGTATGATGTATTGTTTGCACTCT TCAGCAAATTGGAAAGGACATGTGAACTTATATATTTGACACAACCCAGCAGTT CGATATCTACTGAAATAAATTCTGCATTGGTGCTAAAAGTTTCTTGGATCACATT TTTATTAGCTAAAGGGGAAGTATTACAAATGGAAGATGATCTGGTGATTTCATTT CAGTTAATGCTATGTGTCCTTGACTATTTTATTAAACTCTCACCTCCCATGTTGC TCAAAGAACCATATAAAACAGCTGTTATACCCATTAATGGTTCACCTCGAACACC CAGGCGAGGTCAGAACAGGAGTGCACGGATAGCAAAACAACTAGAAAATGATA CAAGAATTATTGAAGTTCTCTGTAAAGAACATGAATGTAATATAGATGAGGTGAA AAATGTTTATTTCAAAAATTTTATACCTTTTATGAATTCTCTTGGACTTGTAACATC TAATGGACTTCCAGAGGTTGAAAATCTTTCTAAACGATACGAAGAAATTTATCTT AAAAATAAAGATCTAGATGCAAGATTATTTTTGGATCATGATAAAACTCTTCAGA CTGATTCTATAGACAGTTTTGAAACACAGAGAACACCACGAAAAAGTAACCTTG ATGAAGAGGTGAATGTAATTCCTCCACACACTCCAGTTAGGACTGTTATGAACA CTATCCAACAATTAATGATGATTTTAAATTCAGCAAGTGATCAACCTTCAGAAAA TCTGATTTCCTATTTTAACAACTGCACAGTGAATCCAAAAGAAAGTATACTGAAA AGAGTGAAGGATATAGGATACATCTTTAAAGAGAAATTTGCTAAAGCTGTGGGA CAGGGTTGTGTCGAAATTGGATCACAGCGATACAAACTTGGAGTTCGCTTGTAT TACCGAGTAATGGAATCCATGCTTAAATCAGAAGAAGAACGATTATCCATTCAAA ATTTTAGCAAACTTCTGAATGACAACATTTTTCATATGTCTTTATTGGCGTGCGC TCTTGAGGTTGTAATGGCCACATATAGCAGAAGTACATCTCAGAATCTTGATTCT GGAACAGATTTGTCTTTCCCATGGATTCTGAATGTGCTTAATTTAAAAGCCTTTG ATTTTTACAAAGTGATCGAAAGTTTTATCAAAGCAGAAGGCAACTTGACAAGAGA AATGATAAAACATTTAGAACGATGTGAACATCGAATCATGGAATCCCTTGCATG GCTCTCAGATTCACCTTTATTTGATCTTATTAAACAATCAAAGGACCGAGAAGGA CCAACTGATCACCTTGAATCTGCTTGTCCTCTTAATCTTCCTCTCCAGAATAATC ACACTGCAGCAGATATGTATCTTTCTCCTGTAAGATCTCCAAAGAAAAAAGGTTC AACTACGCGTGTAAATTCTACTGCAAATGCAGAGACACAAGCAACCTCAGCCTT CCAGACCCAGAAGCCATTGAAATCTACCTCTCTTTCACTGTTTTATAAAAAAGTG TATCGGCTAGCCTATCTCCGGCTAAATACACTTTGTGAACGCCTTCTGTCTGAG CACCCAGAATTAGAACATATCATCTGGACCCTTTTCCAGCACACCCTGCAGAAT GAGTATGAACTCATGAGAGACAGGCATTTGGACCAAATTATGATGTGTTCCATG TATGGCATATGCAAAGTGAAGAATATAGACCTTAAATTCAAAATCATTGTAACAG CATACAAGGATCTTCCTCATGCTGTTCAGGAGACATTCAAACGTGTTTTGATCAA AGAAGAGGAGTATGATTCTATTATAGTATTCTATAACTCGGTCTTCATGCAGAGA CTGAAAACAAATATTTTGCAGTATGCTTCCACCAGGCCCCCTACCTTGTCACCA ATACCTCACATTCCTCGAAGCCCTTACAAGTTTCCTAGTTCACCCTTACGGATTC CTGGAGGGAACATCTATATTTCACCCCTGAAGAGTCCATATAAAATTTCAGAAG GTCTGCCAACACCAACAAAAATGACTCCAAGATCAAGAATCTTAGTATCAATTG GTGAATCATTCGGGACTTCTGAGAAGTTCCAGAAAATAAATCAGATGGTATGTA ACAGCGACCGTGTGCTCAAAAGAAGTGCTGAAGGAAGCAACCCTCCTAAACCA CTGAAAAAACTACGCTTTGATATTGAAGGATCAGATGAAGCAGATGGAAGTAAA CATCTCCCAGGAGAGTCCAAATTTCAGCAGAAACTGGCAGAAATGACTTCTACT CGAACACGAATGCAAAAGCAGAAAATGAATGATAGCATGGATACCTCAAACAAG GAAGAGAAATGA SEQ ID NO: 2 Translation (928 aa): MPPKTPRKTAATAAAAAAEPPAPPPPPPPEEDPEQDSGPEDLPLVRLEFEETEEPD FTALCQKLKIPDHVRERAWLTWEKVSSVDGVLGGYIQKKKELWGICIFIAAVDLDEM SFTFTELQKNIEISVHKFFNLLKEIDTSTKVDNAMSRLLKKYDVLFALFSKLERTCELI YLTQPSSSISTEINSALVLKVSWITFLLAKGEVLQMEDDLVISFQLMLCVLDYFIKLSP PMLLKEPYKTAVIPINGSPRTPRRGQNRSARIAKQLENDTRIIEVLCKEHECNIDEVK NVYFKNFIPFMNSLGLVTSNGLPEVENLSKRYEEIYLKNKDLDARLFLDHDKTLQTD SIDSFETQRTPRKSNLDEEVNVIPPHTPVRTVMNTIQQLMMILNSASDQPSENLISYF NNCTVNPKESILKRVKDIGYIFKEKFAKAVGQGCVEIGSQRYKLGVRLYYRVMESML KSEEERLSIQNFSKLLNDNIFHMSLLACALEVVMATYSRSTSQNLDSGTDLSFPWIL NVLNLKAFDFYKVIESFIKAEGNLTREMIKHLERCEHRIMESLAWLSDSPLFDLIKQS KDREGPTDHLESACPLNLPLQNNHTAADMYLSPVRSPKKKGSTTRVNSTANAET QATSAFQTQKPLKSTSLSLFYKKVYRLAYLRLNTLCERLLSEHPELEHIIWTLFQHTL QNEYELMRDRHLDQIMMCSMYGICKVKNIDLKFKIIVTAYKDLPHAVQETFKRVLIKE EEYDSIIVFYNSVFMQRLKTNILQYASTRPPTLSPIPHIPRSPYKFPSSPLRIPGGNIYI SPLKSPYKISEGLPTPTKMTPRSRILVSIGESFGTSEKFQKINQMVCNSDRVLKRSA EGSNPPKPLKKLRFDIEGSDEADGSKHLPGESKFQQKLAEMTSTRTRMQKQKMND SMDTSNKEEK SEQ ID NO: 3 Gene Name: E2F1 (E2F transcription factor 1) Gene ID: 1869 Protein ID: NP_005216-1 CCDS: CCDS13224.1 E2F1 Nucleotide Sequence (1314 nt): ATGGCCTTGGCCGGGGCCCCTGCGGGCGGCCCATGCGCGCCGGCGCTGGAG GCCCTGCTCGGGGCCGGCGCGCTGCGGCTGCTCGACTCCTCGCAGATCGTCA TCATCTCCGCCGCGCAGGACGCCAGCGCCCCGCCGGCTCCCACCGGCCCCG CGGCGCCCGCCGCCGGCCCCTGCGACCCTGACCTGCTGCTCTTCGCCACACC GCAGGCGCCCCGGCCCACACCCAGTGCGCCGCGGCCCGCGCTCGGCCGCCC GCCGGTGAAGCGGAGGCTGGACCTGGAAACTGACCATCAGTACCTGGCCGAG AGCAGTGGGCCAGCTCGGGGCAGAGGCCGCCATCCAGGAAAAGGTGTGAAAT CCCCGGGGGAGAAGTCACGCTATGAGACCTCACTGAATCTGACCACCAAGCGC TTCCTGGAGCTGCTGAGCCACTCGGCTGACGGTGTCGTCGACCTGAACTGGGC TGCCGAGGTGCTGAAGGTGCAGAAGCGGCGCATCTATGACATCACCAACGTCC TTGAGGGCATCCAGCTCATTGCCAAGAAGTCCAAGAACCACATCCAGTGGCTG GGCAGCCACACCACAGTGGGCGTCGGCGGACGGCTTGAGGGGTTGACCCAG GACCTCCGACAGCTGCAGGAGAGCGAGCAGCAGCTGGACCACCTGATGAATAT CTGTACTACGCAGCTGCGCCTGCTCTCCGAGGACACTGACAGCCAGCGCCTG GCCTACGTGACGTGTCAGGACCTTCGTAGCATTGCAGACCCTGCAGAGCAGAT GGTTATGGTGATCAAAGCCCCTCCTGAGACCCAGCTCCAAGCCGTGGACTCTT CGGAGAACTTTCAGATCTCCCTTAAGAGCAAACAAGGCCCGATCGATGTTTTCC TGTGCCCTGAGGAGACCGTAGGTGGGATCAGCCCTGGGAAGACCCCATCCCA GGAGGTCACTTCTGAGGAGGAGAACAGGGCCACTGACTCTGCCACCATAGTGT CACCACCACCATCATCTCCCCCCTCATCCCTCACCACAGATCCCAGCCAGTCTC TACTCAGCCTGGAGCAAGAACCGCTGTTGTCCCGGATGGGCAGCCTGCGGGC TCCCGTGGACGAGGACCGCCTGTCCCCGCTGGTGGCGGCCGACTCGCTCCTG GAGCATGTGCGGGAGGACTTCTCCGGCCTCCTCCCTGAGGAGTTCATCAGCCT TTCCCCACCCCACGAGGCCCTCGACTACCACTTCGGCCTCGAGGAGGGCGAG GGCATCAGAGACCTCTTCGACTGTGACTTTGGGGACCTCACCCCCCTGGATTT CTGA SEQ ID NO: 4 Translation (437 aa): MALAGAPAGGPCAPALEALLGAGALRLLDSSQIVIISAAQDASAPPAPTGPAAPAAG PCDPDLLLFATPQAPRPTPSAPRPALGRPPVKRRLDLETDHQYLAESSGPARGRG RHPGKGVKSPGEKSRYETSLNLTTKRFLELLSHSADGVVDLNWAAEVLKVQKRRIY DITNVLEGIQLIAKKSKNHIQWLGSHTTVGVGGRLEGLTQDLRQLQESEQQLDHLM NICTTQLRLLSEDTDSQRLAYVTCQDLRSIADPAEQMVMVIKAPPETQLQAVDSSE NFQISLKSKQGPIDVFLCPEETVGGISPGKTPSQEVTSEEENRATDSATIVSPPPSS PPSSLTTDPSQSLLSLEQEPLLSRMGSLRAPVDEDRLSPLVAADSLLEHVREDFSG LLPEEFISLSPPHEALDYHFGLEEGEGIRDLFDCDFGDLTPLDF SEQ ID NO: 5 PRMT5 siRNA sequence CCG CUA UUG CAC CUU GGA A SEQ ID NO: 6 E2F-1 siRNA sequence: AAC UCC UCG CAG AUC GUC AUC Examples Example 1 The effect of PRMT5 and E2F-1 in growth control was evaluated in U2OS cells. When an analysis of cell growth was performed, the inhibitory effect of PRMT5 was evident when cell growth was measured in the context of a colony formation assay, where PRMT5 siRNA caused a dramatic reduction in growth after 10 days, which was rescued upon co-depletion of E2F-1 (Figure 1a). Protein levels of PRMT5 and E2F1 are shown in Figure 1b. Silencing of PRMT5 activity, with gene-specific siRNA, results in cell death through apoptosis. Moreover, this cell death requires E2F1 activity, as co- silencing E2F1 and PRMT5 rescues the cell death and allows cells to continue growing (Figure 1a). Example 2 Tumour cells that lack the E2F1 gene are less sensitive to PRMT5 inhibition mediated by AT101. In colorectal cancer and breast cancer cell lines where E2F1 has been deleted using CRISPR technology, depletion of E2F1 desensitises cells to PRMT5 inhibition (Figure 2 (a) and (b), indicating that E2F1 is a positive measure for response to PRMT5 inhibition. Example 3 Tumour cells that lack the tumour supressor protein pRb gene are more sensitive to PRMT5 inhibition mediated by AT101. In breast cancer and bone cancer cell lines where pRb has been deleted using CRISPR technology, depletion of pRb sensitises cells to PRMT5 inhibition (Figure 3 (a) and (b), indicating that pRb is a negative measure for response to PRMT5 inhibition. Example 4 Tumour cells that lack the E2F1 gene are less sensitive to PRMT5 inhibition mediated by GSK3326595. In colorectal cancer and breast cancer cell lines where E2F1 has been deleted using CRISPR technology, depletion of E2F1 desensitises cells to GSK3326595 PRMT5 inhibition (Figure 4 (a) and (b)), indicating that E2F1 is a positive measure for response to GSK3326595 mediated PRMT5 inhibition. Example 5 Tumour cells that lack the E2F1 gene are less sensitive to PRMT5 inhibition mediated by PF06939999. In colorectal cancer and breast cancer cell lines where E2F1 has been deleted using CRISPR technology, depletion of E2F1 desensitises cells to PF06939999 PRMT5 inhibition (Figure 5 (a) and (b)), indicating that E2F1 is a positive measure for response to PF06939999 mediated PRMT5 inhibition. Example 6 Tumour cells that lack the E2F1 gene are less sensitive to PRMT5 inhibition mediated by JNJ64619178. In the breast cancer cell line T-47D where E2F1 has been deleted using CRISPR technology, depletion of E2F1 desensitises cells to JNJ64619178 PRMT5 inhibition (Figure 6) indicating that E2F1 is a positive measure for response to JNJ64619178 mediated PRMT5 inhibition. Example 7 Tumour cells that lack the E2F1 gene are less sensitive to PRMT5 inhibition mediated by LLY-283. In the breast cancer cell line T-47D where E2F1 has been deleted using CRISPR technology, depletion of E2F1 desensitises cells to LLY-283 PRMT5 inhibition (Figure 7) indicating that E2F1 is a positive measure for response to LLY- 283 mediated PRMT5 inhibition. Example 8 Tumour cells that lack the tumour supressor protein pRb gene are more sensitive to PRMT5 inhibition mediated by GSK3326595. In breast cancer cancer cell lines where pRb has been deleted using CRISPR technology, depletion of pRb sensitises cells to GSK3326595 PRMT5 inhibition (Figure 8), indicating that pRb is a negative measure for response to GSK3326595 mediated PRMT5 inhibition. Example 9 Tumour cells that lack the tumour supressor protein pRb gene are more sensitive to PRMT5 inhibition mediated by PF06939999. In breast cancer cancer cell lines where pRb has been deleted using CRISPR technology, depletion of pRb sensitises cells to PF06939999 PRMT5 inhibition (Figure 9), indicating that pRb is a negative measure for response to PF06939999 mediated PRMT5 inhibition. Material and Methods MTT assay T-47D cells were maintained in growth medium (RPMI 1640 supplemented with 10% v/v heat inactivated fetal bovine serum and cultured at 37°C, 5% CO2. U2OS, MCF7 and HCT116 cells were maintained in growth medium (DMEM supplemented with 10% v/v heat inactivated fetal bovine serum) and cultured at 37° C, 5% CO2. Under assay conditions, cells were incubated in assay medium (RPMI 1640 or DMSO supplemented with 10% v/v heat inactivated fetal bovine serum and 100 units/mL penicillin-streptomycin) at 37° C under 5% CO2. For the assessment of the effect of compounds on the proliferation of the cancer cell lines, exponentially growing cells were plated into 96-well plates overnight at a density of 1,000 cells/well in a final volume of 100μl of cell growth medium. The next day the cells were dosed with compounds (T-992, GSK3326595, LLY-283, PF-06939999 and JNJ64619178) (quadruplicate ten-point 5-fold serial dilutions in DMSO), beginning at 100µM. After addition of compounds, assay plates were incubated for 8 days at 37° C, 5% CO2, relative humidity 90%. NAD(P)H-dependent cellular oxidoreductase enzyme activity was measured by adding 100µl thiazolyl blue tetrazolium bromide (MTT; Sigma- Aldrich) to the wells at a final concentration of 5µM and incubated for 2 h at 37C. Next, media was discarded from the wells and the formazan crystals were dissolved in 100µl DMSO by shaking for 15 min. Absorbance was read on the Omega FLUOstar plate reader (BMG Labtech Ltd, Ortenberg, Germany) at a wavelength of 584nM. Data were analysed and IC50 values determined using MARs data analysis software (BMG Labtech Ltd, Ortenberg, Germany). The concentration of compound inhibiting cell viability by 50% was determined using a 4-parametric fit of the normalized dose response curves. Western blot Cells were harvested, washed in PBS, and resuspended in lysis buffer [50 mM Tris pH 7.4, 5 mM EDTA, 0.5% Igepal CA-630 (Sigma, Gillingham, UK), 50 mM NaF, 1 mM DTT, 0.2 mM Na3VO4, 120 mM NaCl, protease inhibitor cocktail]. Total protein concentration was determined by Bradford Assay (Bio-Rad). Whole cell lysates were prepared and lysates were separated by 4-20% SDS-PAGE (Bio-rad) and transferred to PVDF membrane (GE Healthcare, Piscataway, NJ). Membranes were blocked with 5% milk in PBS with 0.2 % Tween 20 for 1h at room temperature. Primary antibodies for actin (Sigma, A2228), E2F1 (CST #3742) and Rb (#9309) were diluted 1:1000 in 5% milk incubated overnight at 4°C. Membranes were washed with PBS-T, incubated with HRP-conjugated secondary antibodies (CST) diluted in PBS-T with 5% milk for 1h at room temperature, washed, and developed using SuperSignal West Dura Chemiluminescent Substrate (Thermo Scientific). Colony formation assay U2OS cells were seeded at a density of 1000 cells/well in a 6-well plate and transfection of siRNA was performed as described in the section below. U2OS cells were allowed to establish colonies over a period of 10 days before ending the experiment. The culturing media was gently aspirated to avoid physically damaging the cells and the plates were briefly rinsed with PBS. Crystal violet (Sigma-Aldrich) stain (0.5%) was applied to the cells for 2 minutes, followed by rinsing with autoclaved deionised water and left to air dry. Plates were scanned and colonies measured and counted using the Gelcount™ Colony Counter (Oxford Optronics). siRNA transfection Oligofectamine reagent (Invitrogen) and siRNA complexes (non-targeting, E2F1 and PRMT5) were incubated separately with OPTI-MEM® I Reduced Serum Media (Gibco®) for 5 minutes at room temperature. The two mixtures were combined and incubated for a further 20 minutes. siRNA transfection mix was added to U2OS cells in a dropwise fashion. Commercial non-targeting siRNA control was from Dharmacon. PRMT5 siRNA sequence: 5’-CCG CUA UUG CAC CUU GGA A-3’ (SEQ ID NO: 5), E2F-1 siRNA sequence: 5’ - AAC UCC UCG CAG AUC GUC AUC-3’ (SEQ ID NO: 6) [sense strands shown]. In experiments involving treatment of more than one siRNA, non-targeting siRNA was included to ensure equal amounts of transfected siRNA across all samples. 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