We are now excited to move this forward in prospective trials of patients with CDK4/6 independent cancers & high leukemia risk. Thank you to the Neil Hirsch Foundation, @break-cancer.bsky.social , @ash.hematology.org , LLS, Edward P. Evans MDS Foundation, NCI, NHLBI, and V Foundation for support.
Similarly, in a mouse model of TP53 mutant clonal hematopoiesis, we found that contemporaneous administration of a CDK4/6 inhibitor with platinum chemotherapy mitigated p53 mutant cell expansion with chemotherapy:
The development of therapy-related myeloid neoplasms is one of the most dangerous complications of cancer-directed therapy. Here we identify across 4 randomized trials that short-term CDK4/6 inhibition mitigates clonal expansion of TP53 mutant hematopoietic cells during cytotoxic chemotherapy.
Excited to announce a new paper out today in Nature Genetics identifying a new approach to mitigate the risk of therapy-related myeloid malignancies in patients with cancer. Collaboration with Kelly Bolton’s lab @kellybolton.bsky.social @washumedicine.bsky.social
www.nature.com/articles/s41...
Thanks so much for having me @uwmadisonrna.bsky.social , Aaron, and the Hoskins lab! I had a great time!
Our phase II trial of Ulixertinib in adults with histiocytosis is open and enrolling so please reach out with any referrals:
clinicaltrials.gov/study/NCT064...
Importantly both mice and patients with class 3 MEK mutations respond to ERK inhibition with Ulixertinib. Through FDA compassionate use and help of @BioMedValley, we treated 5 MEK1 E102_I103del mutant patients with Ulixertinib and saw partial or complete responses:
We then created a conditional knockin mouse model of the most common MEK mutation – MEK1 E102_I103del and fund that these mice develop a high penetrance histiocytosis affecting the skin and hematopoietic organs:
Now across an international cohort of 498 patients we identify that RAF-independent MEK mutations (which are common amongst histiocytosis patients) are associated with progression to MEK inhibition:
Led by Eli Diamond and former Abdel-Wahab lab member (now RutgersCancer) Benjamin Durham + Takeshi Fujino. Prior work by our group led to FDA-approval of vemurafenib for BRAFV600E mutant histiocytosis followed by Cobimetinib for BRAF WT:
www.nature.com/articles/s41...
Excited to announce a new publication from our @mskcancercenter.bsky.social Histiocytosis group identifying a predictor for impaired response to MEK inhibition in histiocytosis patients and potential for ERK inhibition. Out today in @Cancer_Cell.
www.sciencedirect.com/science/arti...
Thanks @adamssperling.bsky.social !
Thanks @paralkarlab.bsky.social !
It turns out that ARHGAP45 also encodes the first identified minor histocompatibility antigen (HA-1) and we present a new cell therapeutic approach to target HA-1 and upregulate ARHGAP45 derived epitopes. Thanks to @LLSusa, @theNCI, @MSKCancerCenter for their support.
Excited to announce a new paper in @aacrjournals.bsky.social with Junwei Shi and Tony Daniyan. We perform screens of GAPs and GEFs in AML and discover a hematopoietic-specific GAP (ARHGAP45) required in a variety of hematologic malignancies:
aacrjournals.org/cancerdiscov...
Now online in Cancer Discovery @aacrjournals.bsky.social: Systematic Evaluation of GAPs & GEFs Identifies a Targetable Dependency for Hematopoietic Malignancies - by Pu Zhang, Zhendong Cao, Anthony Daniyan, Omar Abdel-Wahab, Junwei Shi, et al. doi.org/10.1158/2159...
Excited to announce our annual New York City Edward P. Evans MDS Centers Symposium across @mskcancercenter.bsky.socia & @columbiacancer.bsky.social. This year to be held at @mskcancercenter.bsky.socia. See this flyer below and register here:
forms.fillout.com/t/1wX3dGmym4us
Thanks @raflynn5.bsky.social ! congrats on the cell surface NPM1 paper this week as well.
We are excited to develop this as a novel cell therapy for myeloid leukemia patients with mutations in splicing factors. Thank you to @break-cancer.bsky.social, ASH, LLS, Edward P. Evans MDS Foundation, NCI, NHLBI, and @parkerici.bsky.social for support.
Importantly we were able to identify neoantigen-specific CD8 T cells in patients with active MDS and AML. However, these neoantigen specific T cells had clear evidence of dysfunction, likely explaining the initiation/maintenance of these malignancies.
We now find that MDS and AML patients with mutations in the splicing machinery create endogenous mis-splicing derived immunogenic peptides which are shared across patients (“public”) and were used to isolate tumor-selective TCRs.
In 2021 in collaboration with the Bradley lab we identified that pharmacologic modulation of splicing creates bona fide RNA mis-splicing derived neoantigens which can augment immune checkpoint blockade efficacy in syngeneic solid tumor models:
Mutations in genes encoding RNA splicing factors occur in 50-80% of patients with myelodysplastic neoplasms and create stereotyped changes in RNA splicing consistent across patients.
This is part of a long-standing collaboration with Rob Bradley’s lab
@fredhutch.bsky.social and with amazing TCR discovery expertise from Chris Klebanoff’s lab @klebanofflab.bsky.social @mskcancercenter.bsky.social. Also incredible help from Jeff Molldrem @mdanderson.bsky.social
Excited to announce a new paper out today in @cp-cell.bsky.social discovering RNA mis-splicing derived neoantigens & their cognate T cell receptors (TCRs) as well as characterization of endogenous neoantigen T cells in leukemia patients.
authors.elsevier.com/sd/article/S...
Thanks so much @mikemfernandez.bsky.social ! Congrats on all of your success at #ASH24 and your award!
