Could Rapamycin be an alternative treatment for my condition?
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As with most things around rapamycin, since its off patent there are few human clinical trials outside of the research done in immune suppression 20 years ago.
But my quick search on Pubmed does suggest it may be of value, and something to talk to your doctor about: sirolimus lymphatic leukemia - Search Results - PubMed
Some papers that seem like they may be relevant:
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The role of KDM1A in CLL
The researchers, led by Marco Herling of the University of Leipzig, Germany, carried out a series of experiments using patient data and samples, animal models, and in vitro studies. First, they used mass spectrometry to study patient and control samples, establishing that TCL1A interacts with KDM1A to enhance its activity in B cells, indicating that this could be a mechanism through which increased TCL1A levels in CLL alter the epigenetic signature of B cells. They then compared KDM1A expression levels in data from a prospective clinical trial of two anti-cancer therapies in CLL to explore the enzyme’s relationship with disease outcomes. These results demonstrated that high KDM1A expression was associated with more aggressive disease features and worse clinical outcomes in the group of 337 patients.1
Digging deeper
To further explore the relevance of KDM1A, the researchers studied the effects of Kdm1a knockdown in the CLL mouse model. This showed that the knockdown of Kdm1a resulted in significantly longer overall survival (67 days vs. 39-41 days), more stable white blood cell counts, and decreased leukemic cell counts. Studying the spleens of the animals revealed that this was due to an increased rate of CLL-cell apoptosis coupled with a reduced rate of proliferation. Interestingly, the team showed that the knockdown of Kdm1a did not only have a direct impact on B cells but also helped reshape the tumor microenvironment, impairing features that help support tumor cell proliferation and survival. This potential role for KDM1A in modulating the tumor microenvironment has also been suggested in breast cancer studies.
Additionally, the team compared RNA expression between the two models, discovering that of 1013 differentially expressed genes between the two genotypes, 81% were upregulated in cells from the knockdown model. The team believes this suggests that Kdm1a suppresses global transcriptional activity in murine CLL. In particular, the expression of programmed-cell-death genes was overrepresented in cells from the knockdown model, providing further support for the pro-apoptotic role of KDM1A.1
Finally, to confirm KDM1A as a potential therapeutic target in CLL, the team explored the effect of anti-KDM1A compounds on leukemic cells, revealing that pharmacologic KDM1A inhibition increased histone methylation and induced CLL cell apoptosis. They also demonstrated a synergistic effect between KDM1A inhibitors and the existing therapies - venetoclax and idasanutlin - suggesting anti-KDM1A agents could potentially be used as combination therapies.
White Paper | Beyond Genetics?
KDM1A = LSD1
In chronic lymphocytic leukemia (CLL), epigenetic alterations are considered to centrally shape the transcriptional signatures that drive disease evolution and underlie its biological and clinical subsets. Characterizations of epigenetic regulators, particularly histone-modifying enzymes, are very rudimentary in CLL. In efforts to establish effectors of the CLL-associated oncogene T-cell leukemia 1A (TCL1A ), we identified here the lysine-specific histone demethylase KDM1A to interact with the TCL1A protein in B cells in conjunction with an increased catalytic activity of KDM1A. We demonstrate that KDM1A is upregulated in malignant B cells. Elevated KDM1A and associated gene expression signatures correlated with aggressive disease features and adverse clinical outcomes in a large prospective CLL trial cohort. Genetic Kdm1a knockdown in Eμ-TCL1A mice reduced leukemic burden and prolonged animal survival, accompanied by upregulated p53 and proapoptotic pathways. Genetic KDM1A depletion also affected milieu components (T, stromal, and monocytic cells), resulting in significant reductions in their capacity to support CLL-cell survival and proliferation. Integrated analyses of differential global transcriptomes (RNA sequencing) and H3K4me3 marks (chromatin immunoprecipitation sequencing) in Eμ-TCL1A vs iKdm1a KD*;Eμ-TCL1A* mice (confirmed in human CLL) implicate KDM1A as an oncogenic transcriptional repressor in CLL which alters histone methylation patterns with pronounced effects on defined cell death and motility pathways. Finally, pharmacologic KDM1A inhibition altered H3K4/9 target methylation and revealed marked anti–B-cell leukemic synergisms. Overall, we established the pathogenic role and effector networks of KDM1A in CLL via tumor-cell intrinsic mechanisms and its impacts in cells of the microenvironment. Our data also provide rationales to further investigate therapeutic KDM1A targeting in CLL.
Hi David.
There is an organisation called. The Leukemia & Lymphoma Society® (LLS). They are a global leader in the fight against blood cancer. “The LLS mission: Cure leukemia, lymphoma, Hodgkin disease and myeloma, and improve the quality of life of patients and their families. LLS funds lifesaving blood cancer research around the world, provides free information and support services, and is the voice for all blood cancer patients seeking access to quality, affordable, coordinated care.”
Maybe they could provide some answers?
I have no personal experience of them, besides that they have invested in the same biotech as I have. (Developing antibody treatments in The Leukemia & Lymphoma Society’s Therapy Acceleration Program).
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