Published OnlineFirst January 29, 2016; DOI: 10.1158/2159-8290.CD-NB2016-010
NEWS IN BRIEF she relapsed again after 9 months, with worsening liver metastases and impending liver failure. “There didn’t seem to be any options left, but we decided to do another biopsy,” Shaw says. This time, the researchers found an additional ALK mutation, L1198F, on the same allele as C1156Y. Cell-line studies indicated that L1198F promoted resistance to lorlatinib and other next-generation ALK inhibitors, but unexpectedly restored sensitivity to crizotinib. Treatment with crizotinib was therefore restarted, “although we generally move toward more potent, selective ALK inhibitors, and almost never look back,” Shaw notes. The patient’s recovery was swift; she regained liver function within weeks, and her second response to crizotinib lasted nearly 6 months. Through biochemical and crystallography analyses, the researchers determined that L1198F interferes with lorlatinib’s binding to ALK, but increases crizotinib’s affinity for its target. “We think the enhanced binding due to L1198F negates the increased kinase activity from C1156Y, thereby resensitizing tumor cells to crizotinib,” Shaw explains. “It’s interesting that this subset of NSCLC retains ALK dependency; the tumor keeps modulating the oncogenic driver as we pressure it with different drugs,” says Christine Lovly, MD, PhD, an assistant professor at Vanderbilt Ingram Cancer Center in Nashville, TN. “This study highlights the importance of monitoring tumor heterogeneity and evolution throughout therapy.” “Obtaining repeat biopsies from patients who relapse on targeted therapies, for molecular profi ling, is key,” Shaw adds. “This isn’t standard practice, although I’m seeing more of it. Once blood tests assessing cell-free tumor DNA are validated and become mainstream, we’ll have a more efficient, less invasive way to pinpoint resistance mutations in ALK-positive NSCLC.” Shaw and Lovly also advocate combining ALK inhibitors, which have so far been used as sequential monotherapy, to better keep resistance at bay. “Rational combinations would be particularly useful in the frontline setting, because that’s our first and best chance of achieving the most meaningful response,” Lovly says.
Alice Shaw, MD, PhD, advocates profiling repeat biopsies from patients who relapse on targeted therapies as a way to uncover novel resistance mechanisms in ALK+ NSCLC.
Lorlatinib is still in early-phase studies, but “as we continue to study resistance that emerges, we may see L1198F appear more often,” Shaw says. Meanwhile, she’s struck that this mutation alters the very leucine residue lorlatinib’s designers at Pfizer exploited to enhance the drug’s selectivity for ALK over other kinases. “It’s intriguing, from a chemistry standpoint—how we may be able to anticipate mutations based on a drug’s design, and in doing so, perhaps find ways to overcome them,” she says. –Alissa Poh ■
Expanding Therapy for Neuroendocrine Tumors Results from two phase III studies indicate that the mTOR inhibitor everolimus (Afinitor; Novartis) and the radiopharmaceutical 177LutetiumDOTATATE (Lutathera; Advanced Accelerator Applications) both substantially delay disease progression in patients with advanced neuroendocrine tumors (NET) of the gastrointestinal (GI) tract. The data were presented by Simron Singh, MD, and Jonathan Strosberg, MD, respectively, during the American Society of Clinical Oncology’s Gastrointestinal Cancers Symposium, held in San Francisco, CA, January 21–23. NETs occur most commonly in the GI tract, pancreas, and lungs. Each year, about 8,000 people in the United
States are diagnosed with GI NETs, a subset broadly divided into midgut and non-midgut categories. The former includes tumors originating in the ileum, duodenum, and appendix; the latter encompasses tumors of the stomach, colon, and rectum. Surgery, chemotherapy, or somatostatin analogs (SSA), a standard hormone therapy, are the main treatments. Singh, a medical oncologist at the University of Toronto’s Odette Cancer Center in Canada, reported results from a subgroup analysis of the RADIANT-4 study, in which 175 patients with advanced GI NETs were randomized to receive everolimus or placebo. Sixty of these patients had midgut NETs, and the rest had non-midgut tumors. In both categories, treatment with everolimus improved the median progression-free survival (PFS) by more than 6 months. “This study enrolled both patients who had previously received SSAs, and those who hadn’t,” Singh noted. “Interestingly, everolimus was effective across the board, regardless of pretreatment.” The drug was well tolerated, he added, with the main side effects being mouth inflammation, diarrhea, and fatigue. Strosberg, a medical oncologist at Moffitt Cancer Center in Tampa, FL, reported results from the NETTER-1 study, which evaluated 177LutetiumDOTATATE, an SSA attached to a radiopharmaceutical. This is a type of peptide receptor radionuclide therapy (PRRT), Strosberg said, adding that it has been used to treat thousands of patients in Europe. “It enables the targeted delivery of radiation to tumors expressing somatostatin receptors, which many well-differentiated NETs do in high concentrations.” The study’s 230 patients, all with advanced midgut NETs, had progressed on first-line SSA therapy. They were randomized to receive four 177Lutetium-DOTATATE treatments, or the SSA octreotide (Sandostatin; Novartis). The median PFS in the experimental arm has not been reached, Strosberg reported, “but it’s expected to be longer than 3 years, which is extremely impressive for this population.” By contrast, the median PFS in the control arm was just 8 months. He also noted that 177 Lutetium-DOTATATE’s main side effect, nausea, was “mostly related to
MARCH 2016CANCER DISCOVERY | 221
Downloaded from cancerdiscovery.aacrjournals.org on May 5, 2016. © 2016 American Association for Cancer Research.
Published OnlineFirst January 29, 2016; DOI: 10.1158/2159-8290.CD-NB2016-010
NEWS IN BRIEF the amino acid infusions used to protect the kidneys [from radiation].” PRRT is readily available in Europe because “each hospital with a nuclear medicine center can produce and administer their own radiolabeled SSAs,” Strosberg explained, “while PRRT is less common in the U.S., because there’s been some reluctance to invest in the large randomized studies needed for its regulatory approval, NETs being a rare cancer.” “There’s going to be some debate as to whether this therapy or everolimus should be used for the average patient who progresses on SSAs,” he added, “and I think somatostatin receptors should be considered—if they’re present on a patient’s PET scan, he or she will likely do well on [177Lutetium-DOTATATE].” 177 Lutetium-DOTATATE “represents a new modality of anticancer treatment,” noted Smitha Krishnamurthi, MD, a medical oncologist at Case Comprehensive Cancer Center in Cleveland, OH, “and the positive data on everolimus, along with its good tolerability, are very welcome for a patient population with few therapeutic options.” –Alissa Poh ■
Pathway to Chromosomal Instability Revealed A recently published study reveals an unexpected role for a long noncoding RNA (lncRNA) in maintaining the proper number of chromosomes in cells (Cell 2016;164:69–80). Larger cousins of microRNAs, lncRNAs are transcripts of more than 200 nucleotides with no detectable open reading frames, often with unknown function. The new work shows that one lncRNA, dubbed NORAD (noncoding RNA activated by DNA damage) preserves genome stability by promoting expression of genes involved in DNA repair, replication, and mitosis. Loss of NORAD in human cells results in altered chromosome number, a hallmark of cancer cells. Lead investigator Joshua Mendell, MD, PhD, and colleagues at the University of Texas Southwestern Medical Center in Dallas, set out to identify lncRNAs that regulate the response of cells to DNA damage. They first spotted NORAD among lncRNAs induced
222 | CANCER DISCOVERYMARCH 2016
by treating human and mouse cells with DNA-damaging doxorubicin. Mendell’s team focused on NORAD because, unlike many lncRNAs, it was abundant in many tissues, and its sequence was highly conserved between mouse and human. To probe NORAD function, the researchers inactivated the lncRNA in a human colon cancer cell line and nontransformed human fibroblasts, revealing a surprising phenotype. “All the cells that lose this RNA exhibit a chromosomal instability phenotype, meaning that they have a high frequency of chromosome gain or loss during mitosis,” says Mendell. The researchers went on to show that NORAD is a major binding partner for PUMILIO proteins, an ancient and highly conserved family of cytoplasmic proteins that repress translation of mRNAs. One molecule of NORAD can bind 15 PUMILIO molecules, resulting in inactivation of PUMILIO. After DNA damage, NORAD levels are sufficient to sequester most of the cell’s PUMILIO proteins, allowing beneficial expression of target genes involved in DNA replication, repair, and mitosis. In the NORAD knockout cells, increased repression of target genes by PUMILIO proteins leads to mistakes in chromosome handling and aneuploidy. The work is the first to implicate a lncRNA as well as PUMILIO proteins in the maintenance of chromosome integrity. Whether they play a role in cancer remains to be seen, says Mendell. “We’re interested in whether this pathway is perturbed in cancer, and whether it can influence cancer phenotypes,” he says. Some clues may lie in already-existing expression data from large-scale tumor genetic projects like TCGA, and his team plans to look at that, Mendell says. The work “opens a new area of understanding of where chromosome handling might go awry,” says Maxwell Krem, MD, PhD, of the University of Louisville School of Medicine in Kentucky, who was not involved in the new study. Chromosomal instability is associated with disease prognosis and response to treatment, and attacking pathways that regulate genomic stability could become an important addition to standard chemotherapy in the future, he says. –Pat McCaffrey ■
Vaccinating against HPV: A Call to Action All 69 NCI-designated cancer centers issued a joint statement at the end of January urging health care providers to encourage vaccination against human papillomavirus (HPV). HPV causes the majority of cervical, anal, vaginal, penile, vulvar, and oropharyngeal cancers. According to the Centers for Disease Control and Prevention (CDC), approximately 79 million people in the U.S. are currently infected with HPV. The FDA has approved three safe and effective HPV vaccines to ward off most HPV-related cancers. However, the vaccination rate in the United States stands at about 30% (40% for girls and 21% for boys), which is not only significantly lower than many other countries—including Australia (75%), the United Kingdom (84% to 92%), and Rwanda (93%)—but falls well short of 80%, the goal set by the Healthy People 2020 initiative (www.healthypeople.gov). The focus has been on “the virus being sexually transmitted, rather than HPV vaccines preventing cancer,” says Lisa Richardson, MD, director of the CDC’s division of cancer prevention and control. Meanwhile, this stigma has resulted in “a reluctance among many primary care providers to provide a clear, simple recommendation: ‘Now’s the time for your young adolescent to get vaccinated,’” says Robert Croyle, PhD, director of the NCI’s division of cancer control and population sciences. The vaccine’s efficacy increases the earlier it is given—“it works best in those who haven’t been infected with the virus, which essentially means people who aren’t yet sexually active,” says Gary Gilliland, MD, PhD, president and director of Fred Hutchinson Cancer Research Center in Seattle, WA. As such, children should be vaccinated by age 17, and ideally before they turn 13. However, young men and women up to ages 21 and 26, respectively (who weren’t vaccinated as adolescents), can still protect themselves against infection by completing the three-dose series. “We’re often asked, ‘When are we going to find a cure for cancer?’” observes Patrick Loehrer Sr., MD, director of Indiana University’s Simon Cancer Center in Indianapolis. “The truth is that the
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Published OnlineFirst January 29, 2016; DOI: 10.1158/2159-8290.CD-NB2016-010
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NEWS IN BRIEF she relapsed again after 9 months, with worsening liver metastases and impending liver failure. “There didn’t seem to be any options left, but we decided to do another biopsy,” Shaw says. This time, the researchers found an additional ALK mutation, L1198F, on the same allele as C1156Y. Cell-line studies indicated that L1198F promoted resistance to lorlatinib and other next-generation ALK inhibitors, but unexpectedly restored sensitivity to crizotinib. Treatment with crizotinib was therefore restarted, “although we generally move toward more potent, selective ALK inhibitors, and almost never look back,” Shaw notes. The patient’s recovery was swift; she regained liver function within weeks, and her second response to crizotinib lasted nearly 6 months. Through biochemical and crystallography analyses, the researchers determined that L1198F interferes with lorlatinib’s binding to ALK, but increases crizotinib’s affinity for its target. “We think the enhanced binding due to L1198F negates the increased kinase activity from C1156Y, thereby resensitizing tumor cells to crizotinib,” Shaw explains. “It’s interesting that this subset of NSCLC retains ALK dependency; the tumor keeps modulating the oncogenic driver as we pressure it with different drugs,” says Christine Lovly, MD, PhD, an assistant professor at Vanderbilt Ingram Cancer Center in Nashville, TN. “This study highlights the importance of monitoring tumor heterogeneity and evolution throughout therapy.” “Obtaining repeat biopsies from patients who relapse on targeted therapies, for molecular profi ling, is key,” Shaw adds. “This isn’t standard practice, although I’m seeing more of it. Once blood tests assessing cell-free tumor DNA are validated and become mainstream, we’ll have a more efficient, less invasive way to pinpoint resistance mutations in ALK-positive NSCLC.” Shaw and Lovly also advocate combining ALK inhibitors, which have so far been used as sequential monotherapy, to better keep resistance at bay. “Rational combinations would be particularly useful in the frontline setting, because that’s our first and best chance of achieving the most meaningful response,” Lovly says.
Alice Shaw, MD, PhD, advocates profiling repeat biopsies from patients who relapse on targeted therapies as a way to uncover novel resistance mechanisms in ALK+ NSCLC.
Lorlatinib is still in early-phase studies, but “as we continue to study resistance that emerges, we may see L1198F appear more often,” Shaw says. Meanwhile, she’s struck that this mutation alters the very leucine residue lorlatinib’s designers at Pfizer exploited to enhance the drug’s selectivity for ALK over other kinases. “It’s intriguing, from a chemistry standpoint—how we may be able to anticipate mutations based on a drug’s design, and in doing so, perhaps find ways to overcome them,” she says. –Alissa Poh ■
Expanding Therapy for Neuroendocrine Tumors Results from two phase III studies indicate that the mTOR inhibitor everolimus (Afinitor; Novartis) and the radiopharmaceutical 177LutetiumDOTATATE (Lutathera; Advanced Accelerator Applications) both substantially delay disease progression in patients with advanced neuroendocrine tumors (NET) of the gastrointestinal (GI) tract. The data were presented by Simron Singh, MD, and Jonathan Strosberg, MD, respectively, during the American Society of Clinical Oncology’s Gastrointestinal Cancers Symposium, held in San Francisco, CA, January 21–23. NETs occur most commonly in the GI tract, pancreas, and lungs. Each year, about 8,000 people in the United
States are diagnosed with GI NETs, a subset broadly divided into midgut and non-midgut categories. The former includes tumors originating in the ileum, duodenum, and appendix; the latter encompasses tumors of the stomach, colon, and rectum. Surgery, chemotherapy, or somatostatin analogs (SSA), a standard hormone therapy, are the main treatments. Singh, a medical oncologist at the University of Toronto’s Odette Cancer Center in Canada, reported results from a subgroup analysis of the RADIANT-4 study, in which 175 patients with advanced GI NETs were randomized to receive everolimus or placebo. Sixty of these patients had midgut NETs, and the rest had non-midgut tumors. In both categories, treatment with everolimus improved the median progression-free survival (PFS) by more than 6 months. “This study enrolled both patients who had previously received SSAs, and those who hadn’t,” Singh noted. “Interestingly, everolimus was effective across the board, regardless of pretreatment.” The drug was well tolerated, he added, with the main side effects being mouth inflammation, diarrhea, and fatigue. Strosberg, a medical oncologist at Moffitt Cancer Center in Tampa, FL, reported results from the NETTER-1 study, which evaluated 177LutetiumDOTATATE, an SSA attached to a radiopharmaceutical. This is a type of peptide receptor radionuclide therapy (PRRT), Strosberg said, adding that it has been used to treat thousands of patients in Europe. “It enables the targeted delivery of radiation to tumors expressing somatostatin receptors, which many well-differentiated NETs do in high concentrations.” The study’s 230 patients, all with advanced midgut NETs, had progressed on first-line SSA therapy. They were randomized to receive four 177Lutetium-DOTATATE treatments, or the SSA octreotide (Sandostatin; Novartis). The median PFS in the experimental arm has not been reached, Strosberg reported, “but it’s expected to be longer than 3 years, which is extremely impressive for this population.” By contrast, the median PFS in the control arm was just 8 months. He also noted that 177 Lutetium-DOTATATE’s main side effect, nausea, was “mostly related to
MARCH 2016CANCER DISCOVERY | 221
Downloaded from cancerdiscovery.aacrjournals.org on May 5, 2016. © 2016 American Association for Cancer Research.
Published OnlineFirst January 29, 2016; DOI: 10.1158/2159-8290.CD-NB2016-010
NEWS IN BRIEF the amino acid infusions used to protect the kidneys [from radiation].” PRRT is readily available in Europe because “each hospital with a nuclear medicine center can produce and administer their own radiolabeled SSAs,” Strosberg explained, “while PRRT is less common in the U.S., because there’s been some reluctance to invest in the large randomized studies needed for its regulatory approval, NETs being a rare cancer.” “There’s going to be some debate as to whether this therapy or everolimus should be used for the average patient who progresses on SSAs,” he added, “and I think somatostatin receptors should be considered—if they’re present on a patient’s PET scan, he or she will likely do well on [177Lutetium-DOTATATE].” 177 Lutetium-DOTATATE “represents a new modality of anticancer treatment,” noted Smitha Krishnamurthi, MD, a medical oncologist at Case Comprehensive Cancer Center in Cleveland, OH, “and the positive data on everolimus, along with its good tolerability, are very welcome for a patient population with few therapeutic options.” –Alissa Poh ■
Pathway to Chromosomal Instability Revealed A recently published study reveals an unexpected role for a long noncoding RNA (lncRNA) in maintaining the proper number of chromosomes in cells (Cell 2016;164:69–80). Larger cousins of microRNAs, lncRNAs are transcripts of more than 200 nucleotides with no detectable open reading frames, often with unknown function. The new work shows that one lncRNA, dubbed NORAD (noncoding RNA activated by DNA damage) preserves genome stability by promoting expression of genes involved in DNA repair, replication, and mitosis. Loss of NORAD in human cells results in altered chromosome number, a hallmark of cancer cells. Lead investigator Joshua Mendell, MD, PhD, and colleagues at the University of Texas Southwestern Medical Center in Dallas, set out to identify lncRNAs that regulate the response of cells to DNA damage. They first spotted NORAD among lncRNAs induced
222 | CANCER DISCOVERYMARCH 2016
by treating human and mouse cells with DNA-damaging doxorubicin. Mendell’s team focused on NORAD because, unlike many lncRNAs, it was abundant in many tissues, and its sequence was highly conserved between mouse and human. To probe NORAD function, the researchers inactivated the lncRNA in a human colon cancer cell line and nontransformed human fibroblasts, revealing a surprising phenotype. “All the cells that lose this RNA exhibit a chromosomal instability phenotype, meaning that they have a high frequency of chromosome gain or loss during mitosis,” says Mendell. The researchers went on to show that NORAD is a major binding partner for PUMILIO proteins, an ancient and highly conserved family of cytoplasmic proteins that repress translation of mRNAs. One molecule of NORAD can bind 15 PUMILIO molecules, resulting in inactivation of PUMILIO. After DNA damage, NORAD levels are sufficient to sequester most of the cell’s PUMILIO proteins, allowing beneficial expression of target genes involved in DNA replication, repair, and mitosis. In the NORAD knockout cells, increased repression of target genes by PUMILIO proteins leads to mistakes in chromosome handling and aneuploidy. The work is the first to implicate a lncRNA as well as PUMILIO proteins in the maintenance of chromosome integrity. Whether they play a role in cancer remains to be seen, says Mendell. “We’re interested in whether this pathway is perturbed in cancer, and whether it can influence cancer phenotypes,” he says. Some clues may lie in already-existing expression data from large-scale tumor genetic projects like TCGA, and his team plans to look at that, Mendell says. The work “opens a new area of understanding of where chromosome handling might go awry,” says Maxwell Krem, MD, PhD, of the University of Louisville School of Medicine in Kentucky, who was not involved in the new study. Chromosomal instability is associated with disease prognosis and response to treatment, and attacking pathways that regulate genomic stability could become an important addition to standard chemotherapy in the future, he says. –Pat McCaffrey ■
Vaccinating against HPV: A Call to Action All 69 NCI-designated cancer centers issued a joint statement at the end of January urging health care providers to encourage vaccination against human papillomavirus (HPV). HPV causes the majority of cervical, anal, vaginal, penile, vulvar, and oropharyngeal cancers. According to the Centers for Disease Control and Prevention (CDC), approximately 79 million people in the U.S. are currently infected with HPV. The FDA has approved three safe and effective HPV vaccines to ward off most HPV-related cancers. However, the vaccination rate in the United States stands at about 30% (40% for girls and 21% for boys), which is not only significantly lower than many other countries—including Australia (75%), the United Kingdom (84% to 92%), and Rwanda (93%)—but falls well short of 80%, the goal set by the Healthy People 2020 initiative (www.healthypeople.gov). The focus has been on “the virus being sexually transmitted, rather than HPV vaccines preventing cancer,” says Lisa Richardson, MD, director of the CDC’s division of cancer prevention and control. Meanwhile, this stigma has resulted in “a reluctance among many primary care providers to provide a clear, simple recommendation: ‘Now’s the time for your young adolescent to get vaccinated,’” says Robert Croyle, PhD, director of the NCI’s division of cancer control and population sciences. The vaccine’s efficacy increases the earlier it is given—“it works best in those who haven’t been infected with the virus, which essentially means people who aren’t yet sexually active,” says Gary Gilliland, MD, PhD, president and director of Fred Hutchinson Cancer Research Center in Seattle, WA. As such, children should be vaccinated by age 17, and ideally before they turn 13. However, young men and women up to ages 21 and 26, respectively (who weren’t vaccinated as adolescents), can still protect themselves against infection by completing the three-dose series. “We’re often asked, ‘When are we going to find a cure for cancer?’” observes Patrick Loehrer Sr., MD, director of Indiana University’s Simon Cancer Center in Indianapolis. “The truth is that the
www.aacrjournals.org
Downloaded from cancerdiscovery.aacrjournals.org on May 5, 2016. © 2016 American Association for Cancer Research.
Published OnlineFirst January 29, 2016; DOI: 10.1158/2159-8290.CD-NB2016-010
Expanding Therapy for Neuroendocrine Tumors Cancer Discov 2016;6:221-222. Published OnlineFirst January 29, 2016.
Updated version
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Access the most recent version of this article at: doi:10.1158/2159-8290.CD-NB2016-010
Sign up to receive free email-alerts related to this article or journal. To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at [email protected]. To request permission to re-use all or part of this article, contact the AACR Publications Department at [email protected].
Downloaded from cancerdiscovery.aacrjournals.org on May 5, 2016. © 2016 American Association for Cancer Research.
