Can a lit­tle known drug in As­traZeneca's pipeline make a come­back as a PARP add-on? Yale sci­en­tists ex­plain how

As­traZeneca’s cedi­ranib may not have made the cut as a sin­gle agent to treat ovar­i­an can­cer, but Yale re­searchers think it could serve as a pow­er­ful add-on to am­pli­fy the ef­fects of PARP in­hibitors.

Pe­ter Glaz­er

The the­o­ry has been that cedi­ranib works by block­ing the for­ma­tion of new blood ves­sels, thus de­priv­ing tu­mors of the nu­tri­tion and oxy­gen nec­es­sary to live and grow. But in a mouse tri­al, a team out of Pe­ter Glaz­er’s lab found that the drug al­so di­rect­ly af­fects path­ways in­volved in DNA re­pair — a po­ten­tial­ly more use­ful func­tion.

The sci­en­tists set out to ex­plain some un­ex­pect­ed re­sults from a re­cent Phase II study, in which a com­bi­na­tion of cedi­ranib with Lyn­parza (ola­parib) im­proved pro­gres­sion-free sur­vival com­pared to Lyn­parza alone (16.5 ver­sus 8.2 months, haz­ard ra­tio 0.50; p = 0.007) in pa­tients with re­lapsed plat­inum-sen­si­tive ovar­i­an can­cer. More im­por­tant­ly, a sub­set of pa­tients in the tri­al with­out doc­u­ment­ed BR­CA1/2 mu­ta­tions demon­strat­ed su­pe­ri­or PFS as well as over­all sur­vival. That’s sur­pris­ing giv­en that a BR­CA mu­ta­tion is of­ten seen as a pre­req­ui­site for As­traZeneca and Mer­ck’s star PARP in­hibitor to work.

Alan­na Ka­plan

Af­ter ex­plor­ing the phe­nom­e­na in mice and cell cul­ture, Glaz­er and his team — in­clud­ing lead in­ves­ti­ga­tor Alan­na Ka­plan — con­clud­ed that cedi­ranib has a di­rect ef­fect on ho­mol­o­gy-di­rect­ed re­pair, a mech­a­nism that can­cer cells can ma­nip­u­late. The down-reg­u­la­tion, they write in Sci­ence Trans­la­tion­al Med­i­cine, hap­pens on­ly in tu­mors but not bone mar­row cells, which has tra­di­tion­al­ly been the dose-lim­it­ing fac­tor for PARP drugs.

“Un­like ola­parib, it doesn’t di­rect­ly block a DNA re­pair mol­e­cule, stop­ping DNA from stitch­ing it­self back to­geth­er. It af­fects the reg­u­la­tion by which DNA re­pair genes are ex­pressed,” Glaz­er added in a state­ment.

More specif­i­cal­ly, cedi­ranib does so through platelet-de­rived growth fac­tor re­cep­tor (PDGFR) in­hi­bi­tion, ac­ti­va­tion of pro­tein phos­phatase 2A (PP2A), and E2F tran­scrip­tion fac­tor 4 (E2F4)/RB tran­scrip­tion­al core­pres­sor like 2 (RB2/p130)–me­di­at­ed re­pres­sion of BR­CA1/2 and RAD51 gene ex­pres­sion.

The ef­fects are not lim­it­ed to Lyn­parza, ei­ther; cedi­ranib al­so sen­si­tized cells to an­oth­er PARP in­hibitor de­vel­oped by Pfiz­er, BMN673 (ta­la­zoparib).

Back in 2016 As­traZeneca pulled an EMA ap­pli­ca­tion for cedi­ranib and axed a monother­a­py pro­gram for the drug. Its web­site now lists a Lyn­parza/cedi­ranib com­bo as a project in a piv­otal phase, with a US fil­ing in ovar­i­an can­cer planned for 2020.

The Yale re­searchers will move on to in­ves­ti­gate whether this new­found syn­thet­ic lethal­i­ty — the idea of killing can­cer cells more ef­fec­tive­ly by tar­get­ing two genes at the same time — in oth­er can­cer types.


Im­age Source: Shut­ter­stock

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