“Obesity is linked to prostate cancer, scientists know, but it’s not clear why. On Monday, researchers reported a surprising connection.
“When prostate cancers lose a particular gene, they become tiny fat factories, a team at Beth Israel Deaconess Medical Center in Boston reported in a paper published in Nature Genetics.
“Then the cancers spread from the prostate, often with deadly effect. Prostate cancers that have not lost that gene also can spread, or metastasize — in mice, at least — but only if they have a ready source of fat from the diet.”
“Prostate cancer is the second most commonly diagnosed cancer among Canadian men but only about half of these cancers grow rapidly enough to require treatment.
“However, determining which prostate cancers need to be treated can be tricky because it’s hard to predict through biopsy which cancers will eventually become harmful. In fact, because biopsies often do not yield accurate information, between a third and half of patients initially diagnosed with harmless prostate cancers are likely to be “upgraded” to potentially harmful cancers within a year or two of diagnosis.
“A research team led by Dr. David Berman, a professor in the Department of Pathology and Molecular Medicine at Queen’s, and Dr. Tamara Lotan from Johns Hopkins University discovered that the decline of a specific protein within a tumour could help identify the tumours requiring treatment.
” ‘We have shown that a tumour-suppressing protein called phosphatase and tensin homolog, or PTEN, is lost most frequently in prostate tumours that will become harmful and require treatment,’ says Dr. Berman. ‘The team from Johns Hopkins has done a terrific job of making this test more reliable and valid and applicable to prostate cancer and to other forms of cancer.’ Currently, the Gleason Grading system is used to determine the harmful potential of prostate cancers. Scores usually range from 6 to 10, with lower numbers often indicating cancers that are unlikely to become harmful.”
For many years it has been known that cancer cells store and use fat molecules differently from the way normal cells do. Fat molecules, also called lipids, tend to accumulate in so-called lipid droplets within cells. These droplets can be seen under a microscope with special staining methods, but the precise mixture of the different kinds of lipids in an individual cell is difficult to analyze. Now, researchers have developed a new imaging technique called Raman spectromicroscopy, which allows for detailed analysis of lipids on a single-cell level. Continue reading…
“A link between prostate cancer aggressiveness and the accumulation of a compound produced when cholesterol is metabolized in cells has been discovered, findings that could bring new diagnostic and treatment methods. Findings also suggest that a class of drugs previously developed to treat atherosclerosis might be repurposed for treatment of advanced prostate cancer. The research involved analysis of clinical samples harvested from prostate cancer patients, specialized cell lines and mice.”
Someone had to do it; now it looks like Novartis may be the first. The pharma company’s new series of clinical trials, SIGNATURE (also known as, ‘bring the protocol to the patient,’ or ‘P2P’), is recruiting patients with different cancers to receive investigational targeted drugs selected to match the distinct genetic changes found in each patient’s tumor. Continue reading…
Durban VM, Deuker MM, Bosenberg MW, Phillips W, McMahon M. The Journal of Clinical Investigation. Nov 1, 2013.
“Malignant melanoma is frequently driven by mutational activation of v-raf murine sarcoma viral oncogene homolog B1 (BRAF) accompanied by silencing of the phosphatase and tensin homology (PTEN) tumor suppressor. Despite the implied importance of PI3K signaling in PTENNull melanomas, mutational activation of the gene encoding the catalytic subunit of PI3Kα (PIK3CA), is rarely detected. Since PTEN has both PI3-lipid phosphatase–dependent and –independent tumor suppressor activities, we investigated the contribution of PI3K signaling to BRAFV600E-induced melanomagenesis using mouse models, cultured melanoma cells, and PI3K pathway–targeted inhibitors. These experiments revealed that mutationally activated PIK3CAH1047R cooperates with BRAFV600E for melanomagenesis in mice. Moreover, pharmacological inhibition of PI3Ks prevented growth of BRAFV600E/PTENNull melanomas in vivo and in tissue culture. Combined inhibition of BRAFV600E and PI3K had more potent effects on the regression of established BRAFV600E/PTENNull melanomas and cultured melanoma cells than individual blockade of either pathway. Surprisingly, growth of BRAFV600E/PIK3CAH1047R melanomas was dependent on the protein kinase AKT; however, AKT inhibition had no effect on growth of BRAFV600E/PTENNull melanomas. These data indicate that PTEN silencing contributes a PI3K-dependent, but AKT-independent, function in melanomagenesis. Our findings enhance our knowledge of how BRAFV600E and PI3K signaling cooperate in melanomagenesis and provide preclinical validation for combined pathway–targeted inhibition of PI3K and BRAFV600E in the therapeutic management of BRAFV600E/PTENNull melanomas.”
The mutation BRAFV600E is found in conjunctival melanoma at approximately the same frequency as in cutaneous melanoma. The presence of this mutation should make this rare type of melanoma eligible for treatment with the BRAF inhibitors vemurafenib and dabrafenib, which have significant antitumor activity in BRAF V600E–mutant cutaneous melanoma. However, there are no published data on the use of BRAF inhibitors in patients with conjunctival melanoma. This letter reports that treatment of a patient with metastatic conjunctival melanoma using vemurafenib did not halt disease progression and had to be discontinued. This could be due to the previously described frequent loss of the tumor suppressor PTEN and consequent activation of the PI3K pathway in conjunctival melanoma, warranting further studies of combination treatment of these tumors with BRAF and PI3K or AKT inhibitors.
Haffner MC, Mosbruger T, Esopi DM, Fedor H, et al. The Journal of Clinical Investigation. Oct 25, 2013.
“Recent controversies surrounding prostate cancer overtreatment emphasize the critical need to delineate the molecular features associated with progression to lethal metastatic disease. Here, we have used whole-genome sequencing and molecular pathological analyses to characterize the lethal cell clone in a patient who died of prostate cancer. We tracked the evolution of the lethal cell clone from the primary cancer to metastases through samples collected during disease progression and at the time of death. Surprisingly, these analyses revealed that the lethal clone arose from a small, relatively low-grade cancer focus in the primary tumor, and not from the bulk, higher-grade primary cancer or from a lymph node metastasis resected at prostatectomy. Despite being limited to one case, these findings highlight the potential importance of developing and implementing molecular prognostic and predictive markers, such as alterations of tumor suppressor proteins PTEN or p53, to augment current pathological evaluation and delineate clonal heterogeneity. Furthermore, this case illustrates the potential need in precision medicine to longitudinally sample metastatic lesions to capture the evolving constellation of alterations during progression. Similar comprehensive studies of additional prostate cancer cases are warranted to understand the extent to which these issues may challenge prostate cancer clinical management.”
Liu R, Li X, Gao W, Zhou Y, et al. Clinical Cancer Research. Sep. 18, 2013.
“Purpose: The ER chaperone GRP78 translocates to the surface of tumor cells and promotes survival, metastasis, and resistance to therapy. An oncogenic function of cell surface GRP78 has been attributed to the activation of phosphoinositide 3-kinase (PI3K) pathway. In this study, we intend to use a novel anti-GRP78monoclonal antibody (MAb159) to attenuate PI3K signaling and inhibit tumor growth and metastasis. Experimental Design: MAb159 was characterized with biochemical and biological analyses. Its anti-tumor activity was tested in cancer cell culture, tumor xenograft models, tumor metastasis models, and spontaneous tumor models. Cancer cells and tumor tissues were analyzed for PI3K signaling modulation by MAb159. For clinical development, MAb159 was humanized and this humanized MAb159 was further characterized and used in imaging studies. Results: MAb159 specifically recognized surface GRP78, triggered GRP78 endocytosis, and localized to tumors but not normal organs in vivo. MAb159 inhibited tumor cell proliferation and enhanced tumor cell death both in vitro and in tumor xenograft models. It also inhibited tumor metastasis. In MAb159 treated tumors, PI3K signaling was inhibited without compensatory MAPK pathway activation. Furthermore, MAb159 halted or reversed tumor progression in the spontaneous PTEN loss driven prostate and leukemia tumor models. Humanized MAb159, which retains high affinity, tumor specific localization, and the anti-tumor activity, was non-toxic in mice and had favorable pharmacokinetics. Conclusions: These results indicate that the GRP78 specific antibody MAb159 modulates PI3K pathway, inhibits tumor growth and metastasis, and therefore has potential to be a novel cancer therapeutic. Humanized MAb159 will enter human trials shortly.”