TP53 gives competitive advantage in low dose BCL2 inhibitor treatment

[PulsedTherapy]

ashpublications.org/blood/a...

Anyone else see this paper on TP53. Looks like a very well done study. It's mainly for AML, but should have carryover to CLL.

What they found was that if you don't have enough BCL2 inhibitor kill the TP53 clonal population, it will become dominant, as the TP53 mutation gives it survival advantages even though it is upstream of BCL2.

They theorizing by regulating BAK/BKT downstream of BCL2.

The argue that this competitive survival advantage of the TP53 is the reason why we see shorter PFS for TP53 patients.

Also, very interestingly, if they used BCL2 inhibitor plus MCL1, the effectiveness was nearly complete.

I haven't seen an BCL2/MCL1 trial yet, but sounds like it would be an excellent one to do.

[PulsedTherapy]

Looks like there is a trial on the MCL1 alone and with venetoclax, but I didn't see results:

clinicaltrials.gov/study/NC...

[AussieNeil Partner Administrator in reply to PulsedTherapy]

That's a phase 1 study where the effectiveness of the drug and its toxicity are evaluated by researchers for different blood cancers. Only 70 patients registered and there's no patient number breakdown by the AML, CLL and MDS categories included. Looks like they decided not to pursue CLL or MM per my emphasis and concentrated on AML; "Part 1 of the study is monotherapy dose escalation. Closed November 2020 Part 2 of the study is monotherapy expansion groups for relapsed/refractory chronic lymphocytic leukaemia (CLL), AML/ myelodysplastic syndromes (MDS), and multiple myeloma (MM). Closed November 2020 Part 3 is a sequential, dose-escalation study of the combination of AZD5991 and venetoclax in subjects with relapsed/refractory AML."

Note the referenced study that initiated this clinical trial phase 1 research; Discovery of Mcl-1-specific inhibitor AZD5991 and preclinical activity in multiple myeloma and acute myeloid leukemia

pubmed.ncbi.nlm.nih.gov/305...

That fits with what was noted in table 1 of the roughly concurrently written paper I referenced earlier.

Neil

[PulsedTherapy in reply to AussieNeil]

Roger that, I did read elsehwere while investigating this, MCL1 overexpression does seem to happen in TP53 relapse. So maybe an application there.

[AussieNeil Partner Administrator]

"CLL cells in all patients express high levels of BCL2 and typically much lower levels of MCL1 or BCLxL", which is why MCL1 inhibitors aren't used for CLL treatment, per table 1, BCL2-targeting or MCL1-targeting bone fide BH3 mimetics currently in clinical trials

From BCL2 and MCL1 inhibitors for hematologic malignancies (2021)

ashpublications.org/blood/a...

The authors are from the Walter and Eliza Hall Institute of Medical Research, where BCL-2 research that resulted in the development of venetoclax began in the late 1990s, plus associated Australian CLL centres of excellence.

You need to be very careful about extrapolating myeloid neoplasm research to lymphoid neoplasm research. More importantly in this case, MCL1 expression varies with the maturity stage of B cell neoplasms, which is why it is used in clinical trials for multiple myeloma (MM), a mature B cell (plasma cell) neoplasm, but not CLL.

Neil

[PulsedTherapy in reply to AussieNeil]

Great explanation, thanks AussieNeil