Methods of identifying risk of bevacizumab-induced proteinuria and hypertension

Abstract

The disclosure relates to methods of identifying subjects at risk of developing bevacizumab-induced toxicities such as proteinuria and/or hypertension involving measuring nucleic acid or gene mutations in a sample obtained from the subject.

1 . A method of treating a subject, the method comprising the steps of:
 a. determining the risk of developing one or more VEGF-pathway inhibitor-induced toxicities in the subject based upon the presence or absence of a mutation in one or more nucleic acids in a sample obtained from a subject, wherein the subject is undergoing therapy or is a candidate for therapy with a VEGF-pathway inhibitor; and   b. modulating therapy with a VEGF-pathway inhibitor and/or providing the subject with one or more supportive therapies based upon the determined risk of developing one or more VEGF-pathway inhibitor-induced toxicities in the subject.   
     
     
         2 . The method of  claim 1 , wherein the method further comprises detecting the mutation in the one or more nucleic acids in a sample obtained from the subject. 
     
     
         3 . The method of  claim 1 , wherein the detecting of the mutation in one or more nucleic acids in the sample comprises detecting a single nucleotide polymorphism (SNP) in the one or more nucleic acids in the sample. 
     
     
         4 . The method of  claim 3 , wherein the SNP is located in a gene provided in Table 8 or Table 9. 
     
     
         5 . The method of  claim 4 , wherein the gene is KCNAB1, PIK3R5, DNAH5 TRIO, or TTMA. 
     
     
         6 . The method of  claim 4 , wherein the mutation in the gene is a mutation that lowers expression of KCNAB1 relative to wildtype. 
     
     
         7 . The method of  claim 3 , wherein the SNP is selected from the SNPs provided in Table 4, Table 5, Table 6, Table 7, Table 10, Table 11, Table 12, Table 13, rs444904, and rs427554. 
     
     
         8 . The method of  claim 3 , wherein the SNP is selected from the group consisting of rs339947, rs12482855, rs13135230, rs2350620, rs11662763, rs6770663, rs408130, rs418173, rs12482855, rs444904, and rs427554. 
     
     
         9 . The method of  claim 8 , wherein
 a. the mutation is SNP rs6770663 and wherein the base identified at rs6770663 is a guanine,   b. the mutation is SNP rs444904 and wherein the base identified at rs444904 is a an adenine,   c. the mutation is rs427554 and wherein the base identified at rs427554 is an adenine,   d. the mutation is SNP rs339947 and wherein the base identified at rs339947 is an adenine, and/or   e. the mutation is SNP rs11662763 and the base identified at rs11662763 is an adenine.   
     
     
         10 . The method of  claim 1 , wherein the one or more VEGF-pathway inhibitor-induced toxicities are selected from proteinuria, hypertension, or both. 
     
     
         11 . The method of  claim 10 , comprising providing the subject with one or more supportive therapies when the subject is determined to have a high risk of developing proteinuria, hypertension, or both. 
     
     
         12 . The method of  claim 11 , wherein the one or more supportive therapies include one or more anti-hypertensive agents, one or more proteinuria medications, or a combination thereof. 
     
     
         13 . The method of  claim 12 , wherein the anti-hypertensive agent or proteinuria medication is in a class of drug selected from the group consisting of diuretics, beta blockers, alpha and beta blockers, calcium channel blockers, Angiotensin-converting enzyme (ACE) inhibitors, angiotensin II receptor antagonists (ARBs), adrenergic receptor antagonists, vasodilators, renin inhibitors, aldosterone receptor antagonists, alpha-2 adrenergic receptor agonists, central alpha-2 agonists and other centrally acting drugs, and endothelin receptor blockers. 
     
     
         14 . (canceled) 
     
     
         15 . The method of  claim 11 , wherein the supportive therapy comprises blood pressure monitoring and/or monitoring for proteinuria. 
     
     
         16 . The method of  claim 11 , wherein the subject is treated with the supportive therapy prior to or concurrently with the VEGF pathway inhibitor. 
     
     
         17 . (canceled) 
     
     
         18 . (canceled) 
     
     
         19 . (canceled) 
     
     
         20 . (canceled) 
     
     
         21 . The method of  claim 1 , wherein modulating therapy with the VEGF pathway inhibitor comprises reducing the total number of doses of the VEGF inhibitor. 
     
     
         22 . The method of  claim 1 , wherein modulating therapy with the VEGF pathway inhibitor comprises reducing the dosing frequency of the VEGF inhibitor. 
     
     
         23 . (canceled) 
     
     
         24 . (canceled) 
     
     
         25 . (canceled) 
     
     
         26 . The method of  claim 1 , wherein the VEGF-pathway inhibitor is selected from the group consisting of bevacizumab, bevacizumab-awwb, bevacizumab-bvzr, ranibizumab, aflibercept, ziv-aflibercept, lenalidomide, lenvatinib, ramucirumab, cabozantinib, pazopanib, sunitinib malate, regorafenib, axitinib, tipiracil and trifluridine, ponatinib, vandetanib, sorafenib, everolimus, thalidomide, temsirolimus, interferon alfa, interferon alfa-2B, interferon alfa-N3, peginterferon alfa-2B, peginterferon alfa-2A, rhEndostatin, cediranib, semaxanib, pomalidomide, alitretinoin, imiquimod, sinecatechins, vismodegib, sonidegib, pegaptanib sodium, dexamethasone intravitreal implant, fluocinolone acetonide, conbercept, brolucizumab-dbll, selpercatinib, nintedanib, apatinib, and motesanib. 
     
     
         27 . (canceled) 
     
     
         28 . A method for treating or preventing a VEGF pathway inhibitor-induced toxicity in a subject in need of treatment with a VEGF pathway inhibitor, the method comprising
 (i) identifying the subject as having a mutation in the gene KCNAB1 and   (ii) treating the subject with one or more prophylactic therapies for the toxicity.   
     
     
         29 . A method for treating a subject having a disease or disorder associated with neovascularization or angiogenesis, the method comprising
 (i) identifying the subject as having a mutation in the gene KCNAB1;   (ii) treating the subject with an anti-hypertensive agent; and   (iii) treating the subject with a VEGF pathway inhibitor.   
     
     
         30 . (canceled)