To Al, Robin P et al regarding inhibition of PIK3/Akt (sorry, not natural)

[Lani]

For those running out of options and looking for something already on the market, and for those trying to optimize the options available:

The medication octeotride is utilized in, among other things, the nonoperative treatment of pancreatic endocrine tumors:

[Cancer Research 66, 1576-1582, February 1, 2006]
© 2006 American Association for Cancer Research
Cell, Tumor, and Stem Cell Biology

Octreotide, a Somatostatin Analogue, Mediates Its Antiproliferative Action in Pituitary Tumor Cells by Altering Phosphatidylinositol 3-Kinase Signaling and Inducing Zac1 Expression

Marily Theodoropoulou1, Jing Zhang2, Sandra Laupheimer1, Marcelo Paez-Pereda1, Christophe Erneux2, Tullio Florio3, Uberto Pagotto4 and Günter K. Stalla1
1 Department of Endocrinology, Max Planck Institute of Psychiatry, Munich, Germany; 2 Institut de Recherche Interdisciplinaire en Biologie Humaine et Moléculaire, Free University of Brussels, Brussels, Belgium; 3 Department of Oncology, Biology and Genetics, University of Genova, Genova, Italy; and 4 Endocrine Unit, Department of Internal Medicine and Gastroenterology and Center for Applied Biomedical Research, S. Orsola-Malpighi General Hospital, Bologna, Italy

Requests for reprints: Marily Theodoropoulou, Department of Endocrinology, Max Planck Institute of Psychiatry, Kraepelinstrasse 10, D-80804 Munich, Germany. Phone: 0049-89-30622292; Fax: 0049-89-30622605; E-mail: marily@mpipsykl.mpg.de.

Somatostatin limits cell growth by inhibiting the proliferative activity of growth factor receptors. In this study, it is shown that in pituitary tumor cells, the somatostatin analogue octreotide produces its antiproliferative action by inducing the expression the tumor suppressor gene Zac1. ZAC/Zac1 induces cell cycle arrest and apoptosis and is highly expressed in normal pituitary, mammary, and ovarian glands but is down-regulated in pituitary, breast, and ovarian tumors. Knocking down Zac1 by RNA interference abolished the antiproliferative effect of octreotide in pituitary tumor cells, indicating that Zac1 is necessary for the action of octreotide. The effect of octreotide on Zac1 expression was pertussis toxin sensitive and was abolished after transfection with a dominant negative vector for SHP-1. Zac1 is a target of the phosphatidylinositol 3-kinase (PI3K) survival pathway. Octreotide treatment decreased the tyrosine phosphorylation levels of the PI3K regulatory subunit p85, induced dephosphorylation of phosphoinositide-dependent kinase 1 (PDK1) and Akt, and activated glycogen synthase kinase 3ß (GSKß). Therefore, in pituitary tumor cells, somatostatin analogues produce their antiproliferative action by acting on the PI3K/Akt signaling pathway and increasing Zac1 gene expression. (Cancer Res 2006; 66(3): 1576-82)

[al from Canada]

Sorry Lani,
Most of this stuff is way over my head however, I am aware of research done on statins and for the most part, depite high hopes, statins failed to meet primary endpoints.
regards,
Al

[RobinP]

Yes, I am aware that statin drugs inhibit bc cells via Cyclin D inhibition. Of course, PI3K pathway is one of the upstream pathways of p27 and Cyclin D. Lovastatin is one statin that will inhibit cyclin D:

http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=301 (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=301277)77 (http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=301277)


You might note below that inhibition of cyclinD or the Ubiquitin-Ptoteasome Pathway was not sucessful as a single agent. However, perhaps combined with chemotherapy or targeted therapy, inhibitors of this pathway would be sucessful.See article below:

The Ubiquitin-Proteasome Pathway

The ubiquitin-proteasome pathway is involved in the ordered degradation of key cell-cycle regulatory proteins and thus helps to govern transcription, the cell cycle, apoptosis, and angiogenesis. Multiple ubiquitin molecules bind to the protein substrates that are subsequently degraded by the multicatalytic proteasome complex. Inhibition of the proteasome complex has many effects on the cell. Among these are stabilization of p21, p27, and p53, which help to regulate the cell cycle and increase apoptosis as well as I-kappa B (IκB), which inhibits activation of the nuclear transcription factor kappa B (NF-κB). Activation of NF-κB promotes tumor cell survival and resistance to cytotoxic chemotherapy. Proteasome inhibition has been shown to increase chemosensitivity in preclinical models.[50]

PS-341 is a potent and specific inhibitor of the protea-some. Preclinical activity has been observed in breast cancer cell lines. A phase II study of this agent as monotherapy in patients with refractory breast cancer has been reported. There was no significant activity seen in the first 12 patients enrolled, and the study was closed.[51] Further exploration of this agent in combination with chemotherapy is ongoing.

[Lani]

It is a hormone which inhibits the release of growth hormone by the pituitary and is utilized in the treatment of gigantism (acromegaly). It also inhibits the secretion of prolactin which also plays a role in differentiation of normal breast cancer cells and has a role in breast cancer growth. It also acts as a neurotransmitter in the brain, where its function is less well understood

Receptors for growth hormone and prolactin are present on many breast cancer cells--I am unaware if there have been any studies to try to see if they are particularly associated with her2 breast cancer cells.

Briefly:

"Somatostatin is a neurotransmitter/hormone with a wide range of biologial functions [ 5 ]. It has an important role in the neuroendocrine system and inhibits secretion of growth hormone and prolactin in the anterior pituitary. It also inhibits secretion in the intestine (including gastric acid in the stomach), pancreatic acinar cells and pancreatic beta-cells, stimulates absorption in the intestine and modulates smooth muscle contractility. In the CNS, it is a neurotransmitter activating a hyperpolarising K + current and inhibiting Ca 2+ influx, and is believed to play important roles in regulating locomotor activity and cognitive function. Receptor subtypes were originally proposed on the basis of functional and radio-ligand binding studies, and cloning has now confirmed the presence of at least 4 subtypes."

Octeotride is an analog of somatostatin and is being used in the treatment of a variety of diseases, thus it is available for "off label" use

I was only trying to provide "food for thought" especially for those who have run out of options

[al from Canada]

Dear Lani,

There can't be enough "food for thought" when it comes to this evil disease. As I said, this abstract is over my head and I guess my misinterpretation confirms this and thaks for clarifying this. .
How does one go about obtaining this drug?

Thanks,
Al

[Lani]

It is available for the treatment of gigantism and neuroendocrine tumors. I think it was Gina who said she keeps an endocrinologist in consultation at all times since this disease effects and is effected by numerous systems within the body, including the endocrine system.

I am not an oncologist, but if one's oncologist has run out of ideas, run this by him/her and/or ask him/her to run this by an endocrinologist or even better a gastroenterologist treating neuroendocrine tumors.

I think one thing which prompted me to post this out of the blue, was the post which reprinted the lamentation of the doctor regarding the failure of our system to try things on those "on their last legs"

It seems those on this website are into "creative cooking" with their supplements and might be willing to accept some "creative cooking" with "off-label drugs" when they are on their last legs.


If one's oncologist has run out of ideas, perhaps they might be open to "creativity" IF AN EXISTING DRUG FOR A DIFFERENT DISEASE WORKING THROUGH A SIMILAR MECHANISM MIGHT MAKE SENSE IN THEIR SETTING.

Any idea may be better than none.

I will try to look up the side effects of octeotride and post if I can.

Lani

[RobinP]

Lani, sorry your right about this drug being a hormone. However, I've never seen any research on it for bc. On the other hand, statins have been linked with breast cancer and decreased risk.
http://www.breastcancer.org/research_diet_052605a.html

[Lani]

and somatostatin analog octreotide--now I am totally confused:


: Regul Pept. 2005 Dec 19; [Epub ahead of print] Related Articles, Links

Somatostatin inhibits dendritic cell responsiveness to Helicobacter pylori.

Kao JY, Pierzchala A, Rathinavelu S, Zavros Y, Tessier A, Merchant JL.

Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, 6520A MSRB 1, 1150 West Medical Center Drive, Ann Arbor, MI 48109-0650, USA.

Somatostatin is a regulatory peptide found in abundance in the stomach. We have previously shown that somatostatin is required for IL-4-mediated resolution of Helicobacter pylori gastritis. In the current study, we hypothesize that somatostatin acts directly on antigen-presenting cells in the stomach to lessen the severity of gastritis. To test this hypothesis, we first show that CD11c+ dendritic cells are present in the infected tissue of mice with H. pylori-induced gastritis. Pretreatment of bone marrow-derived dendritic cells with somatostatin results in decreased IL-12 production, and lower splenocyte proliferation induced by H. pylori-stimulated dendritic cells. Furthermore, octreotide, a somatostatin analogue, is more potent than somatostatin in suppressing IL-12 release by H. pylori-stimulated dendritic cells through an NF-kappaB-independent pathway. In addition, IL-4 stimulates somatostatin secretion from dendritic cells. In conclusion, somatostatin inhibits dendritic cell activation by H. pylori; a possible mechanism by which IL-4 mediates resolution of gastritis. We suggest that octreotide may be effective in treating immune-mediated diseases of the stomach.

PMID: 16375983 [PubMed - as supplied by publisher]

Again, it may be good at inhibiting PIK3 but bad at suppressing Il 12 release

but the mechanism for IL12 release from dendritic cells may be different when the stimulus is a bacteria like H pylori than cancer.

The danger of oversimplification...but then again, it might be useful...