10 New Clues to Causes of Cachexia

ecent research has provided new tumors and cachexia. In one, a poly- ­“clinicians would probably first want clues to the causes of cachexia. clonal antibody that specifically neu- to find out if the protein is elevated in In one, an animal study now tralizes PTHrP almost completely certain cancers, and determine which online ahead of print in Nature prevented cachexia, while untreated patients would be good candidates for

oncology-times.com (Rdoi:10.1038/nature13528), symptoms animals became mildly cachexic. a clinical trial.” • of cachexia improved or were prevented In the second experiment, the an- The first author of the study is when mice were given an antibody that tibody treatment prevented the loss Serkan Kir, PhD, of the Spiegelman lab blocked the effects of the parathyroid hor- of muscle mass and improved muscle and Robert Black Fellow at the Damon mone-related protein (PTHrP), known to function, while control animals devel- Runyon Foundation. be secreted by tumor cells. oped severe muscle-wasting. Barrett Rollins, MD, PhD, Dana- The researchers, led by Bruce “You would have expected, based Farber’s Chief Scientific Officer, said Spiegelman, PhD, the Stanley J. on our first experiments in cell culture, the report “provides a new roadmap

August 10, 2014 Korsmeyer Professor of Cell Biology and that blocking PTHrP in the mice would for developing a rational, mechanisti-

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Medicine at Harvard Medical School reduce browning of the fat,” Spiegelman cally based treatment for this incred- and Dana-Farber Cancer Institute, said said in a news release. “But we were sur- ibly ­debilitating condition that occurs the findings are the first to explain in prised that it also affected the loss of in such a large number of our pa- detail how PTHrP switches on a ther- muscle mass, and improved health.” tients. Until now we’ve had no truly mogenic process in fatty tissues, result- The research suggests that PTHrP effective way to reverse this horrible ing in unhealthy weight loss. alone does not directly cause muscle complication.” This tumor-derived protein stimu- wasting, yet blocking the protein’s ac- The current strategy, he noted, is to lated “beige” or brown fat cells mixed tivity prevents it, he explained. Thus, give appetite stimulants and nutrient with stored white fat in the body, caus- the role of PTHrP “is definitely not the supplements, along with medications to

Oncology Times ing the white fat to brown—that is, to whole answer” to the riddle of cachexia, counteract some of the molecular path- generate heat and cause weight loss but may be a necessary part, while other ways believed to underlie the ­wasting pro- even when the animals were at rest. factors are also involved. cess, but those have only limited success. The team carried out two experi- He said that before trying the Another study, by an international ments with mice that developed lung ­anti-PTHrP antibody in humans, team of researchers and now online in Cell Metabolism (doi.org/10.1016/j. cmet.2014.06.011), found evidence that brown fat is key to the process of cachexia. The team, led by Erwin Wagner, iPad Extra! PhD, of the National Cancer Research Centre in Madrid, found that in mice and patients with cancer-associated ca- WATCH: In a video on the chexia, white fat undergoes significant iPad edition of this issue cre- changes and turns into calorie-burning ated by the Spanish National brown fat. The transformation leads Cancer Research Centre, see to increased energy consumption and more about the clinical sig- organ-wasting. nificance of the findings and the strategy that may stimulate weight gain and Inflammation was also found muscle strength. to play an important role in turn- ing white fat into brown fat during cancer-associated cachexia, which sug- OT To receive our iPad issues, download the free Oncology Times app gests a potential therapeutic target, the Video from the App Store today! Visit http://bit.ly/OT-iPadApp, search ­researchers said in a news release. Anti- News in the App Store, or follow the link on oncology-times.com. inflammatory therapies, including the continued on page 11

GOVINDAN design of the study. Unfortunately, this Continued from page 9 study was not powered or designed to “I urge my colleagues to genotype patients test the hypothesis that patients with EGFR-mutant stage IB-IIII NSCLC with NSCLC on a regular basis at the time would benefit from erlotinib following surgical resection and standard postop- of initial diagnosis and when possible at the erative therapy. A large national study time of relapse in clearly defined molecular (ALCHEMIST trial) being planned to address the role of molecularly subsets (EGFR mutant, ALK positive) ­targeted therapy in surgically resected EGFR-mutant NSCLC (with erlotinib following targeted therapies so that patients or placebo) and ALK-positive NSCLC can be enrolled in appropriate clinical trials.” (crizotinib or placebo) will likely open for enrollment in late summer or early fall of this year. nation ­therapies without a clearly (EGFR mutant, ALK positive) follow- I am pleased to note the emergence identified set of biomarkers. I would ing targeted therapies so that patients of a number of salvage therapy urge my ­colleagues to genotype pa- can be enrolled in ­appropriate clinical ­options for patients with EGFR- tients with NSCLC on a regular basis trials. I do not see a role for targeted mutant and ALK-positive NSCLC. It at the time of initial diagnosis and therapies in patients with completely is highly ­unlikely that we will make when possible at the time of relapse in resected NSCLC in routine clinical O substantial gains with empiric combi- clearly defined molecular subsets practice. T 11 Takeaways from the ASCO Annual Meeting Oncology Times from Gordon McVie

t this year’s ASCO Annual doesn’t add very much to trastuzumab. 3 cancers when treated with chemora- Meeting, I was presented The other one, well, pretty predictive, diation: There has been a trend to give

with a yellow ribbon that that aromatase inhibitors are a bit bet- adjuvant , but new data •

said “35 year member,” some- ter than tamoxifen. from a randomized trial suggests that August 10, 2014 thingA that produced mixed feelings, but In this case it was exemestane in is not actually adding anything except does give me the authority to say that younger women with hormone-sen- toxicity. this was a good ASCO! We’ve had some sitive breast cancer combined with Then there are a number of drugs less exciting ones in the past, but this ovarian suppression: Exemestane being tested in advanced non-small cell was one that really impressed. was found to be superior to tamoxi- ; most of them are not much fen. Now that is important if you’re better than what we’ve got and that’s in Western countries where you can not saying very much, sadly. •

Prostate Cancer afford exemestane, but it should However in the REVEL Phase III oncology-times.com Let’s start with the two hormone-­ be noted that for a lot of the world study, ramucirumab came up with J. GORDON MCVIE, sensitive cancers—the big ones, specifi- tamoxifen is still the gold standard and docetaxel as being better than docetaxel MD, is Senior Consultant cally. I think we may have a change of it looks as if 10 years of tamoxifen is in terms of survival, and that’s an un- in Research for the practice here because a big Phase III better than a lesser duration. usual finding: an extension of survival European Institute of study, E3805 from Dana Farber, showed On the topic of ovarian suppres- in advanced non-small cell lung cancer. Oncology and Managing that in adjuvant treatment of prostate sion for breast cancer, LHRH analogue Editor of ecancer. cancer, docetaxel plus the usual treat- suppression of the ovaries with gosere- ment, androgen-deprivation therapy lin showed a really quite encouraging (ADT), was better than ADT—and that ­effect. It was seen to protect the ovaries Over the last couple of years in ovarian it is significantly better. in young, premenopausal women who cancer we have seen anti-angiogenesis So I think if this is going to be rolled received chemotherapy, and I think drugs looking interesting. Their ability out, and I hope it will be, we’re going to this is also on its way to becoming a to prolong survival has been good news, have to make some changes in the way ­standard of therapy. especially for platinum-resistant patients. that urologists talk to medical oncolo- At this meeting we saw the anti-­ gists and the way that multidisciplinary angiogenesis drug cediranib being tested teams tackle this new challenge. Lung Cancer with the PARP-inhibitor olaparib versus Inevitably there was good follow-up After the hormone-sensitive cancers, olaparib alone. A positive effect was data on the two new kids on the block let’s deal with the other big one: lung seen on progression-free survival for the in castration-resistant prostate can- cancer. There, to my astonish- combination versus the solo drug. cer (CRPC). The first one was ment, was small-cell lung abiraterone, and the data cancer. We’ve heard very continues to be good, little about small- Colorectal Cancer with good long-term cell lung cancer in In colorectal cancer, another one of the response rates, and the last 20 years, big ones, there was not a great deal of that is really good but here we had news, although a number of drugs look news. a ­demonstration like they may have some activity down The second that even in exten- the line. was enzalutamide, sive disease, irradi- There was, however, an important which was the other ating the primary clarification for oncologists who see a drug that hit the tumour was a good lot of patients with colorectal cancer. headlines last year at idea. It’s the same in We have agreed that it doesn’t seem ASCO and also continues other cancers: get the bulk to make much difference if you use to show good data. disease down and you can have FOLFIRI or FOLFOX—you choose However, neither of them are an effect even on distant metastases. your combination according to the pa- ­curative, and it’s not clear which one There was also an interesting paper tient’s status and other comorbidities. you should use first. What seemed suggesting that primary cranial irradia- Now it seems that it doesn’t matter to emerge was that neither is good in tion (PCI), was not necessary in small- whether you go for bevacizumab or second line; they’re each better in first cell lung cancer in cases where there cetuximab: In a randomized trial they line. Inevitably there was a combination wasn’t a visible metastasis on an MRI both look the same. So you—and your study of abiraterone plus enzalutamide, scan. This is good news, telling us that patient—choose which one of these which was really exciting. It wasn’t a big instead of giving everybody the toxicity drugs will give the best side effects pro- study, and it wasn’t a randomized study, of PCI—assuming they have achieved file according to existing comorbidities but it did show that this was an exciting some sort of remission with chemother- like existing hypertension, etc. way forward in the treatment of CRPC. apy and radiotherapy—that you can check the brain status with MRI, and if it is negative, then there is no need to go Melanoma Breast Cancer on with prophylactic cranial irradiation. In the less-frequent cancers, there were Now on to breast cancer: A couple of In non-small cell lung cancer, there some dramatic results presented. Two really big studies from IBCSG, one of were a couple of important findings: years ago at ASCO it was melanoma all them pretty disappointing—lapatinib The first was in stage 2B and stage continued on page 12

CACHEXIA “Our data suggest that inhibition browning at early stages of cancer de- Continued from page 10 of the browning of white fat repre- velopment could help to predict sents a promising approach to ame- which patients are going to develop nonsteroidal anti-inflammatory drug liorate the severity of cachexia in cachexia and would thus be good sulindac, ameliorated the severity of cancer patients,” Wagner said. “In ad- candidates to benefit from a preven- O cachexia in mice. dition, identifying biomarkers of tive treatment.” T