(? ready for prime time)--predicting which bc patients would benefit from metformin

[Lani]

note: "potentially" benefiting from metformin

UK: New test identifies cancer patients to benefit from 10p-a-day diabetes drug
[University of Manchester (UK)]

Scientists have developed a new test which can identify which breast cancer patients could benefit from a 10p-a-day diabetes drug.

They used a new method based on the 'food' cancer cells eat to predict which patients would have poor prognosis. They suggest these patients could benefit from metformin, a cheap and safe diabetes drug that could be a revolutionary cancer treatment.

The findings come from the Breakthrough Breast Cancer Research Unit at The University of Manchester and Thomas Jefferson University in the USA and are published today (Friday) in the journal Cell Cycle.

Professor Michael Lisanti, from the Breakthrough Breast Cancer Research Unit at The University of Manchester, said: "We've shown that the saying, 'you are what you eat' holds true for cancer. The food cancer cells consume is crucial to how well a patient does and what treatment they need.

"If cancer cells are consuming high-energy food, this makes a tumour more aggressive and harder to treat. However, they could benefit from metformin, which cuts off this fuel supply. There is more work to do but this test could be an important new way of tailoring treatments to patients need, across a range of cancers."

Professor Lisanti's team first looked at cells in the laboratory and fed them high-energy food, known as lactates and ketones. They found which genes were expressed based on this fuel supply, and developed a gene signature based on this.

They then looked at 219 hormonal breast cancer patients and studied which cancer cells fed on ketones and lactates. This food comes both from cancer cells and healthy cells nearby. They found those patients with cancer cells that consumed high levels of ketones and lactates were more likely to have their disease return, for it to spread to other organs and to die. The test combines the gene signature with the ketone and lactate food supply. This could both show which patients are likely to have a poor prognosis - with those same patients potentially benefiting from metformin.

Professor Anthony Howell, Director of the Breakthrough Breast Cancer Research Unit in Manchester, said: "This is terrifically exciting. It is a step towards having each patient get the right treatment for them - what we call personalised medicine. We are looking at a new way to separate patients based on who should respond well to the treatments we have, and who might need something different.

"It is particularly encouraging that some of those treatments might already be in the doctor's drug cabinet, and cheap to prescribe. We have some way to go but we hope that drugs like metformin will be saving lives of breast cancer patients over the next few years."

ABSTRACT: Glycolytic cancer associated fibroblasts promote breast cancer tumor growth, without a measurable increase in angiogenesis: Evidence for stromal-epithelial metabolic coupling
[Cell Cycle]
Previously, we proposed a new model for understanding the Warburg effect in tumorigenesis and metastasis. In this model, the stromal fibroblasts would undergo aerobic glycolysis (a.k.a., the Warburg effect)—producing and secreting increased pyruvate/lactate that could then be used by adjacent epithelial cancer cells as "fuel" for the mitochondrial TCA cycle, oxidative phosphorylation, and ATP production. To test this model more directly, here we used a matched set of metabolically well-characterized immortalized fibroblasts that differ in a single gene. CL3 fibroblasts show a shift towards oxidative metabolism, and have an increased mitochondrial mass. In contrast, CL4 fibroblasts show a shift towards aerobic glycolysis, and have a reduced mitochondrial mass. We validated these differences in CL3 and CL4 fibroblasts by performing an unbiased proteomics analysis, showing the functional upregulation of 4 glycolytic enzymes, namely ENO1, ALDOA, LDHA and TPI1, in CL4 fibroblasts. Many of the proteins that were upregulated in CL4 fibroblasts, as seen by unbiased proteomics, were also transcriptionally upregulated in the stroma of human breast cancers, especially in the patients that were prone to metastasis. Importantly, when CL4 fibroblasts were co-injected with human breast cancer cells (MDA-MB-231) in a xenograft model, tumor growth was dramatically enhanced. CL4 fibroblasts induced a >4-fold increase in tumor mass, and a near 8-fold increase in tumor volume, without any measurable increases in tumor angiogenesis. In parallel, CL3 and CL4 fibroblasts both failed to form tumors when they were injected alone, without epithelial cancer cells. Mechanistically, under co-culture conditions, CL4 glycolytic fibroblasts increased mitochondrial activity in adjacent breast cancer cells (relative to CL3 cells), consistent with the "Reverse Warburg Effect". Notably, Western blot analysis of CL4 fibroblasts revealed a significant reduction in caveolin-1 (Cav-1) protein levels. In human breast cancer patients, a loss of stromal Cav-1 is associated with an increased risk of early tumor recurrence, metastasis, tamoxifen-resistance, and poor clinical outcome. Thus, loss of stromal Cav-1 may be an effective marker for predicting the "Reverse Warburg Effect" in the stroma of human breast cancer patients. As such, CL4 fibroblasts are a new attractive model for mimicking the "glycolytic phenotype" of cancer-associated fibroblasts. Nutrients derived from glycolytic cancer associated fibroblasts could provide an escape mechanism to confer drug-resistance during anti-angiogenic therapy, by effectively reducing the dependence of cancer cells on a vascular blood supply.

[Ellie F]

Lani-wonder if this holds true for ER- but her2 +? Would certainly volunteer for any trials here in England that clarified the issue.

Ellie

[Ceesun]

Good info. Lani, are you in the scientific field as your profession? Are you a bc patient? Ceesun

[Lani]

more

Jefferson researchers unlock key to personalized cancer medicine using tumor metabolism

Thomas Jefferson University researchers used gene signatures and energy metabolism to predict clinical outcome, rather than gene mutations

PHILADELPHIA—Identifying gene mutations in cancer patients to predict clinical outcome has been the cornerstone of cancer research for nearly three decades, but now researchers at the Kimmel Cancer Center at Jefferson have invented a new approach that instead links cancer cell metabolism with poor clinical outcome. This approach can now be applied to virtually any type of human cancer cell.

The researchers demonstrate that recurrence, metastasis, and poor clinical outcome in breast cancer patients can be identified by simply gene profiling cancer cells that are using ketones and lactate as a food supply.

These findings are reported in the April 15th online issue of Cell Cycle. The investigators are calling this new approach to personalized cancer medicine "Metabolo-Genomics."

High-energy metabolites have long been suspected to "fuel" aggressive tumor cell behavior. The researchers used this premise to generate a gene expression signature from genetically identical cancer cells, but one cell group was fed a diet of high-energy metabolites. These lactate- and ketone-induced "gene signatures" then predicted recurrence, metastasis, and poor survival.

So, it appears that what cancer cells are eating determines clinical outcome, not necessarily new gene mutations.

Michael P. Lisanti, M.D., Ph.D., Professor and Chair of Stem Cell Biology & Regenerative Medicine at Jefferson Medical College of Thomas Jefferson University and a member of the Kimmel Cancer Center at Jefferson, together with other researchers, found that treatment of human breast cancer cells with high-energy metabolites increases the expression of genes associated with normal stem cells, including genes upregulated in embryonic and neural stem cells.

What's more, lactate and ketones were found to promote the growth of normal stem cells, which has critical applications for stem cell transplantation and for a host of different human diseases. It appears that these metabolites increase "stemness" in cancer cells, which drives poorer outcomes.

"Tumors that are using the body's own nutrients (lactate and ketones) as "fuel" have a poorer outcome for patient survival, a behavior that now can be used to predict if a patient is at a high-risk for recurrence or metastasis," Dr. Lisanti said. "This is getting to the heart of personalized cancer medicine. Now, we have identified a panel of biomarkers that directly links cancer metabolism with targeted cancer therapy."

These findings suggest, according to the authors, that high-risk cancer patients (those whose cancer cells use high-energy metabolites) can be treated with new therapeutics that target oxidative mitochondrial metabolism, such as the antioxidant metformin, a drug that is also used to treat diabetes.

"Knowing the gene signatures of patients whose cancer cells are "eating" these metabolites (lactate and ketones) for fuel is a pivotal piece of new information that we can use to diagnose and treat cancer patients," said Martinez-Outschoorn, M.D., of the department of Medical Oncology at Thomas Jefferson University, and the lead author of the paper. "It's not just that we know those patients will have poor survival; we know that those patients are using mitochondrial metabolism, which is the type of energy metabolism that we should be targeting with new anti-cancer drugs."

The researchers propose that this new approach to diagnosis and subsequent treatment be called "Metabolo-Genomics" since it incorporates both cell metabolism and gene transcriptional profiling. This strategy could now be used to direct which patients receive a particular "tailored" anti-metabolic therapy.

Genetic markers, like expression of the mutationally activated HER2 gene, provide biomarkers that can be used to identify breast cancer patients at high-risk for recurrence or metastasis, and to modify their subsequent treatment with targeted therapies (i.e., herceptin, a drug used in aggressive breast cancers). But with "Metabolo-Genomics," it is now about using "global" cancer cell metabolism for these predictions.

"Just by feeding cancer cells a particular energy-rich diet, it changes their character, without introducing mutations or altering their genetic profile," Dr. Lisanti said. "We've only fed them high energy nutrients that help them to use their mitochondria, and this changes their transcriptional profile. It's a new biomarker for "lethal" cancers that we can now treat with the right drugs, such as the anti-oxidant metformin."

Dr. Lisanti and his colleagues believe that tumor metabolism is the new big picture for understand

[pibikay]

Thanks Lani.As usual you have given good news