New study below [1].
15 years ago, with the immediate failure of my prostatectomy, Lupron was offerred as an option. Having read a large number of papers where ADT mostly failed within 18-24 months, & being only 56 at the time, I was puzzled why anyone would rush into a short-lasting palliative therapy that selected for cells that were increasingly difficult to manage.
I was thinking of this as I read the intro to the new paper:
"Increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence of neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy."
My issue is with premature use. The drugs are valuable & doubtless in my future. But how do we deal with treatment-induced cell changes?
The short Abstract will read like Greek to many. Luckily, we have j-o-h-n to translate!
But a key feature of the remarkable reprogramming that occurs to create neuroendocrine PCa cells, is the increase of "intracellular S-adenosyl methionine (SAM) levels to feed epigenetic changes that favor the development of NEPC characteristics.".
I have a number of posts on the SAM system. Briefly, it relys on the diet containing methyl donors such as folate (or folic acid-fortified grain products - or supplements). SAM is the universal methyl donor in the body. PCa cells want to be hypermethylated. Some of the most significant changes that occur in PCa cells are not due to mutation, but rather because of epigenetic silencing via methylation.
In an article on the study [2]:
"Epigenetic patterns associated with NEPC were ... discovered, including an expression of an enzyme called phosphoglycerate dehydrogenase (PHGDH), according to the study. The findings revealed a currently FDA-approved treatment called decitabine {which inhibits epigenetic changes} that may hold promise as an NEPC treatment ..."
[3] "Decitabine is a hypomethylating agent. It hypomethylates DNA by inhibiting DNA methyltransferase." "Decitabine is used to treat myelodysplastic syndromes (MDS)"
Off-label use of Decitabine may prevent the emergence of treatment-induced neuroendocrine PCa, which is far more common than it once was.
-Patrick
[1] ncbi.nlm.nih.gov/pubmed/308...
Cancer Cell. 2019 Feb 11. pii: S1535-6108(19)30052-2. doi: 10.1016/j.ccell.2019.01.018. [Epub ahead of print]
Increased Serine and One-Carbon Pathway Metabolism by PKCλ/ι Deficiency Promotes Neuroendocrine Prostate Cancer.
Reina-Campos M1, Linares JF2, Duran A2, Cordes T3, L'Hermitte A2, Badur MG3, Bhangoo MS4, Thorson PK5, Richards A6, Rooslid T7, Garcia-Olmo DC8, Nam-Cha SY9, Salinas-Sanchez AS10, Eng K11, Beltran H12, Scott DA13, Metallo CM3, Moscat J2, Diaz-Meco MT14.
Author information
1
Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA; Sanford Burnham Prebys Graduate School of Biomedical Sciences, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
2
Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
3
Department of Bioengineering, University of California, San Diego, La Jolla, CA 92093, USA.
4
Division of Hematology-Oncology Scripps Clinic, 10666 N. Torrey Pines Road, La Jolla, CA 92037, USA.
5
Depatment of Pathology, Scripps Clinic Medical Group, 10666 Torrey Pines Road, La Jolla, CA 92037, USA.
6
Proteomics Facility, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
7
Conrad Prebys Center for Drug Discovery, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
8
Centre de Recerca Experimental Biomèdica Aplicada (CREBA), IRBLLEIDA, 25138 Lleida, Spain.
9
Pathology Department, Director of the Research Unit Biobank, University of Castilla-La Mancha, School of Medicine, 02006 Albacete, Spain.
10
Urology Department, Research Unit, University Hospital Complex of Albacete, School of Medicine, 02006 Albacete, Spain.
11
Department of Computational Biomedicine, Weill Cornell Medicine, New York, NY 10065, USA.
12
Department of Medical Oncology, Dana Farber Cancer Institute, Harvard Medical School, Boston, MA 02215, USA.
13
Cancer Metabolism Core, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA.
14
Cancer Metabolism and Signaling Networks Program, Sanford Burnham Prebys Medical Discovery Institute, 10901 N. Torrey Pines Road, La Jolla, CA 92037, USA. Electronic address: mdmeco@sbpdiscovery.org.
Abstract
Increasingly effective therapies targeting the androgen receptor have paradoxically promoted the incidence of neuroendocrine prostate cancer (NEPC), the most lethal subtype of castration-resistant prostate cancer (PCa), for which there is no effective therapy. Here we report that protein kinase C (PKC)λ/ι is downregulated in de novo and during therapy-induced NEPC, which results in the upregulation of serine biosynthesis through an mTORC1/ATF4-driven pathway. This metabolic reprogramming supports cell proliferation and increases intracellular S-adenosyl methionine (SAM) levels to feed epigenetic changes that favor the development of NEPC characteristics. Altogether, we have uncovered a metabolic vulnerability triggered by PKCλ/ι deficiency in NEPC, which offers potentially actionable targets to prevent therapy resistance in PCa.
Copyright © 2019 Elsevier Inc. All rights reserved.
KEYWORDS:
ATF4; PKClambda; aPKC; cancer metabolism; epigenetics; lineage plasticity; mTOR; neuroendocrine; prostate cancer; serine metabolism
PMID: 30827887 DOI: 10.1016/j.ccell.2019.01.018
[2] specialtypharmacytimes.com/...
[3] en.wikipedia.org/wiki/Decit...
Optimizing Bone Health in Prostate Cancer
