Thread by @sue_heavey, (1/13) Please RT: our first #tweetorial!Here's a on our new paper which [...]

Susan Heavey

sue_heavey

Read on Twitter

(1/13) Please RT: our first #tweetorial!

Here's a

on our new paper which is also my 1st time being (joint) last author

Congrats to all, especially superstar med student @LuszczakSabina!

#AcademicTwitter @AcademicChatter @OpenAcademics #womeninSTEM https://www.nature.com/articles/s41598-020-71263-9

Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and...

https://www.nature.com/articles/s41598-020-71263-9

(2/13) In #prostatecancer cell lines & human tissue, co-targeting #PIM & #PI3K #kinases seems promising!

We reckon ~20% of prostate cancer patients could benefit from this approach in future & these tend to be the sicker patients.

Scroll for #science! https://www.nature.com/articles/s41598-020-71263-9

Co-targeting PIM and PI3K/mTOR using multikinase inhibitor AUM302 and a combination of AZD-1208 and...

https://www.nature.com/articles/s41598-020-71263-9

(3/13) Fig1a:

From publicly available data we see that some patients overexpress either the #PIM pathway, the #PI3K pathway, or both. Each of these targets have inhibitors in development, that could theoretically be of benefit to any of these patient groups when combined

(4/13) Fig1b+c:

These patients who could hopefully benefit from this co-targeted approach also happen to tend to be sicker (higher Gleason, lower survival)

(5/13) Fig2:

At the RNA level in 3 #prostatecancer cell lines, inhibition of #PIM/ #PI3K lead to decreased expression of a range of downstream genes, & co-targeted inhibition of both pathways lead to decreased expression of a wider range of #genes, as you might expect!

(6/13) Fig3: At the phospho-protein level, we see similar trends, with the co-targeted approach yielding the most striking inhibition, particularly in the most aggressive cell line (C4-2B) - this was encouraging

(7/13) Fig4: All the inhibitors lead to dose-dependent reductions in proliferation in all cell lines, with the lowest IC50s coming from the triple kinase inhibitor #AUM302, in the nM range.

Nice drug! Thanks: @AumBiosciences @InflectionBio @CNIOStopCancer #drugdevelopment

(8/13) Fig5: In human #exvivo cultures, we see the same story, with improved inhibition of proliferation & induction of apoptosis when we co-target both pathways. Note the conc differences!

This fig is a taster of the work to be expanded on in my new lab #comingsoon #heaveylab

(9/13) limitations: the ex vivo work is only in a few patients, we may have been lucky & we can’t assume this would work so well for everyone – probably only around a fifth will respond like this. Or maybe more… only one way to find out!

(10/13) Next steps: @ProstateUK @MovemberUK have funded us to expand this cohort substantially & carry out detailed molecular work. Much of the collection & culture has already happened, with thanks to @UCLpathology @uclhrobotics

https://prostatecanceruk.org/research/research-we-fund/tld-pf16-004 #fellowship #womeninSTEM

New ways to treat prostate cancer before surgery, and who they’ll work best for

Dr Susan Heavey plans to use a new method of culturing prostate cancer samples in the lab to test new drug combinations, and use cutting edge technologies to predict and monitor response to treatment.

https://prostatecanceruk.org/research/research-we-fund/tld-pf16-004