Treatment strategies for several types of cancer have been transformed by the discovery of â€œtargeted therapies,â€ drugs directed specifically against the genetic mutations that drive tumor growth. So far, these strategies have been relatively unsuccessful when it comes to glioblastoma, the most common and most deadly form of brain tumor affecting adults. Glioblastoma was one of the first tumor types to be analyzed in the Cancer Genome Atlas mega-project, but many of the molecular features of glioblastoma have been difficult to exploit.
For example, about 40 percent of glioblastoma tumors ray ban baratas have extra copies of the EGFR (epidermal growth factor receptor) gene. EGFR provides a pedal-to-the-metal growth signal and is known to play a role in driving the growth of lung and colon cancers as well. But drugs targeted against EGFR that have extended patient survival in lung cancer have shown disappointing results with glioblastoma. The reason: the tumor cells can quickly mutate the EGFR gene or switch to reliance on other growth signals.
Keqiang Ye, PhD and colleagues recently described the discovery of a compound that may be valuable in fighting glioblastoma. The Emory researchers devised a scheme to stop tumor cells from using well-known escape routes to avoid EGFR-based drugs. Their results are published in the journal Science Signaling. Postdoctoral fellow Kunyan He, PhD, is the first author.
The compound they identified inhibits the enzyme JAK2, one of the apparent escape Ray Ban outlet routes taken by glioblastoma cells. The compound can pass the blood-brain barrier and inhibit glioblastoma growth while having low toxicity, the researchers report.
On January 8, Emory University School of Medicine’s Department of Medicine Grand Rounds had an unusual format: a debate between Otis Brawley, MD and John Petros, MD on the topic of PSA testing.
Otis Brawley, MD
Prostate cancer is the second leading cause of cancer death for American men. PSA (prostate specific antigen) is a protein produced by the prostate gland and its levels can be measured by a simple blood test.Â A higher number could indicate prostate cancer, but the test doesnâ€™t differentiate between an aggressive, fast-growing cancer, and one that is so slow-growing it wouldnâ€™t threaten a manâ€™s life.
Brawley, professor of hematology and medical oncology and chief medical officer for the American Cancer Society, led off the debate arguing that studies show PSA testing to be unreliable and possibly leading to too many diagnoses and unnecessary treatment for prostate cancer. Petros, a professor of urology who treats prostate cancer patients, looked at other studies (more details below), which show the PSA test to be a tool that has helped save lives by detecting prostate cancer at earlier stages.
In May 2012, the U.S. Preventive Services Task Force issued a “grade D” rating for PSA screening, saying the practice offers more harms — in terms of complications from PSA-test-driven treatment such as incontinence and blood clots — than benefits. Brawley agreed with this Ray Ban outlet assessment and says heâ€™s not convinced the PSA test saves lives, but he doesnâ€™t rule out its use. He framed this issue this way:
Pretend you are offered the choice of taking a pill that will double the risk of prostate cancer diagnosis from 10 to 20 percent, but could decrease risk of prostate cancer death by one fifth: from 3 to 2.4 percent.Â “Do you feel lucky?” Brawley quipped.
John Petros, MD
As a counterpoint, Petros cited National Cancer Institute epidemiology data indicating that the rate of metastatic prostate cancer has substantially decreased over the last few decades, since prostate cancers are now being diagnosed at an earlier stage. He also went over studies conducted in Sweden (Goteborg) and in Austria (Tyrol), which show significant reductions in prostate cancer-related mortality coming from PSA testing.
Five things Brawley and Petros agreed on:
PSA testing should be performed in the context of a physician-patient relationship, with men making an informed decision about the value of the information they will receive and the associated risks.
Vans in supermarket parking lots â€“ more broadly, community- or employer-based screeningÂ — are not the ideal setting for PSA testing.
The PLCO study, a NCI-sponsored randomized clinical trial to examine the effects of screening on cancer-related mortality, was flawed. In particular, the â€œcontrolâ€ arm had a substantial rate of PSA testing.
Brawley said: â€œSome cancers that are detected early do not pose a threat and do not need to be treated.â€ Similarly, Petros said: â€œProstate cancer can be low risk if safely observed, but high risk forms are lethal. We need to focus on cancers that matter.â€
Biomarkers that are better than PSA alone are needed. Brawley said: â€œWe need a 2013 definition of prostate cancer, informed by genomics, rather than going by what Virchow decided prostate cancer looks like under the microscope 160 years ago.â€
Petros agreed with this last point and noted that more sophisticated tests than PSA already have been identified such as the prostate health index, which measures levels for three forms of PSA and may be more cancer-specific. Research being conducted at Emory by Carlos Moreno and colleagues also moves toward this goal. In 2011, his team published results in the American Journal of Pathology on a panel of biomarkers that can predict prostate cancer outcomes after prostatectomy. The Atlanta Business Chronicle recently had a story on a patent related to Morenoâ€™s research.
Petros said a key question, and one he and Moreno are planning on testing, is whether the same biomarkers could be useful on prostate biopsy samples. This could help make treatment decisions regarding surgery vs radiation. Biopsy-based tests could be combined with data based on urine biomarkers, to get around the problem of tumor heterogeneity and imperfect sampling, Petros said.
For now, Petros said he believes in initiating a conversation about PSA screening with patients 50 and older, or younger if they have risk factors for the disease.Â Â He said the decision to have routine PSA testing, follow-up tests and prostate cancer treatments, is a very individualized process.
â€œIt comes down to, what do you tell the man standing in front of you?â€ he said. â€œYou have to consider where they are in life and what their goals are, and that varies with every man.â€
Before all the excitement about embryonic stem cells, doctors were using hematopoetic â€“ that is, blood-forming — stem cells. Hematopoetic stem cells can replenish all the types of cells in the blood, and are the centerpiece of transplantation as treatment for diseases such as multiple myeloma or leukemia. They can come from two different places: directly from the marrow of a donorâ€™s hip bone, or indirectly from the donorâ€™s blood after a drug nudges the stem cells out of the bone marrow.
Most hematopoetic stem cell transplants in the United States now use the indirect method of obtaining the stem cells. Until this fall, gold-standard randomized clinical trial results were not available to say which method is best for patient outcomes. Winship Cancer Institute hematologist Ned Waller was a key co-author of a study that was published in October in the New England Journal of Medicine addressing this question.
The trial involved 48 centers enrolling 551 patients as part of the Bone Marrow and Clinical Trials Network (BMT CTN).Â Waller helped design the study, and his lab at Winship analyzed the cells in each type of graft as the central core lab for the trial.
The study found no significant difference in the overall Ray Ban Italia survival rate at two years, and no difference in relapse rates or in acute graft-versus-host-disease (GVHD). However, there was a significantly higher rate of chronic GVHD with the use of blood stem cells.
GVHD, a difficult and sometimes life-threatening complication for this type of transplant, involves damage inflicted by the transplant recipientâ€™s new immune system upon the liver, skin and digestive system.
This finding will generate serious discussion among leaders in the transplant field about whether bone marrow or peripheral blood stem cell transplantation is a better treatment option, Waller says. A text Q + A with him follows.
What was surprising about the results of this study?
The equivalent survival was expected, and the increased chronic GvHD in recipients of blood stem cell grafts was suspected. What is surprising is that the relapse rate was similar between the two arms, in spite of the PBSC arm having more chronic GvHD.
The accompanying editorial argues bone marrow should be the standard for unrelated-donor transplants. Do you agree?
Yes, with the exceptions that Fred mentioned: patients with life-threatening infections and patients at high risk for graft rejection.
What are the differences, procedurally, between bone marrow and peripheral blood as sources for hematopoetic stem cell transplant?
Donating bone marrow involves a two or three hour surgical procedure requiring general anesthesia, in which bone marrow is removed from the hip bone with a needle and syringe.Â For peripheral blood stem cells, the donor undergoes five days of injections of granulocyte colony-stimulating factor and then a four-hour apheresis procedure to harvest stem cells from the blood. Blood stem cell donors have bone pain during the 5-day period of cytokine treatment, and bone marrow donors have more discomfort early after donation, but symptoms for both BM and PBSC donors have typically resolved by four weeks after donation.
What proportion of each is now in use here?
Marrow is the graft source in about 25% of recipients of grafts from unrelated donors, 10% in recipients of grafts from related donors.
What proportion of HSCT is unrelated donor?
For allogeneic transplants, about 60% receive grafts form unrelated donors (33% matched related donors and 7% mis-matched related donors).
What kind of information does this study provide oncologists/hematologists about which option to use in which situation?
Marrow should be preferred in recipients of grafts from unrelated donors when the conditioning regimen is myeloablative [substantially damages the patient’s existing bone marrow].
Does it depend on the type of leukemia/myeloma, the age or other conditions of the patient etc?
This study only enrolled patients with acute leukemia and MDS [myelodysplastic syndrome]. It excluded patients with myeloma or lymphoma. Ages included children, adults up to 60.
What other types of studies in this area are being conducted at Winship?
We are studying the role of different constituents in the graft (BM and PBSC) to determine which are most important in shaping transplant outcomes (relapse, GvHD). We have an active pre-clinical research program utilizing mouse models to address specific questions related to engraftment cell homing and specific pathways related to immune activation. In addition, we will participate in a clinical trial of a new way of mobilizing blood stems that avoids the need for five days of G-CSF and uses a CXCR4 antagonist called plerixafor to mobilize PBSC. The properties of the plerixafor-mobilized PBSC may be more similar to BM cells with respect to GvHD.
A recent article in Chemical & Engineering News describes the promising properties of curcumin, a compound derived from turmeric, in models of Alzheimerâ€™s disease.
Curcumin is a component of turmeric
In addition to contributing to curry dishesâ€™ yellow color and pungent flavor, curcumin has been a medicine in India for thousands of years. Doctors practicing traditional Hindu medicine admire turmericâ€™s active ingredient for its anti-inflammatory properties and have used it to treat patients for ailments including digestive disorders and joint pain.
Only in the 1970s did Western researchers catch up with Eastern practices and confirm curcuminâ€™s anti-inflammatory properties in the laboratory. Scientists also eventually determined that the polyphenolic compound is an antioxidant and has chemotherapeutic activity.
Several research groups at Emory are investigating curcumin-related compounds.
Dermatologist Jack Arbiser has been interested in curcumin’s antiangiogenic (inhibiting blood vessel growth) properties for several years and reports that he is studying how the compound is metabolized. Chemist Dennis Liotta and his colleagues have identified relatives of curcumin that are more soluble, and thus could be more easily taken up by the body. In particular, chemist James Snyder has been a key driver in designing and synthesizing curcumin-related compounds used by several investigators at Emory and elsewhere (see figure):
Psychiatrists Thaddeus Pace and Andrew Miller have been testing whetherÂ curcumin relatives may have useful properties with depression. Specifically, the curcumin-related compounds may have the ability to interfere with the connection (YouTube video) between inflammation and depression.
Winship Cancer Institute researcher Mamoru Shoji has been exploring how to target curcumin compounds to tumor-associated endothelial cells by linking themÂ to a clotting factor.Â In the Department of Gynecology and Obstetrics, Friedrich Wieser is examining whether curcumin compounds can be helpful with endometriosis.
Cells sometimes â€œfixâ€ DNA the wrong way, creating an extra mutation, Emory scientists have revealed.
Biologist Gray Crouse, PhD, and radiation oncologist Yoke Wah Kow, PhD, recently published a paper in Proceedings of the National Academy of Sciences that shows how mismatch repair can introduce mutations in nondividing cells. Their paper was recognized by the National Institute of Environmental Health Sciences as an extramural paper of the month. The first author is lead research specialist Gina Rodriguez.
In DNA, a mismatch is when the bases on the two DNA strands do not conform to Watson-Crick rules, such as G with T or A with C. Mismatches can be introduced into DNA through copying errors as well as some kinds of DNA damage.
If the cell â€œfixesâ€ the wrong side, that will introduce a mutation (see diagram). So how does the cell know which side of the mismatch needs to be repaired? Usually mismatch repair is tied to DNA replication. Replication enzymes appear to somehow mark the recently copied strand as being the one to replace — exactly how cells accomplish this is an active area of research.
In some situations, mismatch repair could introduce mutations into DNA.
Overall, mismatch repair is a good thing, from the point of view of preventing cancer. Inherited deficiencies in mismatch repair enzymes lead to an accumulation of mutations and an increased risk of colon cancer and other types of cancer.
But many of the cells in our bodies, such as muscle cells and neurons, have stopped dividing more or less permanently (in contrast with the colon). That means they no longer need to replicate their DNA. Other cells, such as resting white blood cells, have stopped dividing temporarily. Mutations in nondividing cells may have implications for aging and cancer formation in some tissues.
Through clever experimental design, Crouseâ€™s team was able to isolate examples of when mismatch repair occurred in the absence of DNA replication.
As the NIEHS Newsletter notes:
â€œThe researchers introduced specific mispairs into the DNA of yeast cells in a way that let them observe the very rare event of non-strand dependent DNA repair. They found that mispairs, not repaired during replication, sometimes underwent mismatch repair later when the cells were no longer dividing. This repair was not strand dependent and sometimes introduced mutations into the DNA sequence that allowed cells to resume growth. In one case, they observed such mutations arising in cells that had been in a non-dividing state for several days.â€
Although the Emory teamâ€™s research was performed on yeast, the mechanisms of mismatch repair are highly conserved in mammalian cells. Their results could also shed light on a process that takes place in the immune system called somatic hypermutation, in which mutations fine-tune antibody genes to make the most potent antibodies.
Biochemist Paul Doetschâ€™s recent appearance in a Science magazine feature on laboratory leadership led to a conversation with him about the challenges of graduate school.
He emphasized that scientific research is a team sport, and brilliance on the part of the lab head may not yield fruit without a productive relationship with the people in the lab. Doetsch suggested talking with Lydia Morris, a graduate student in the Genetics and Molecular Biology graduate program. Morris has been working in Doetsch’s lab for several years and is about to complete her degree. She has been examining the in vivo distribution of DNA repair proteins.
In this video, Morris and Doetsch talk about the differences between turn-the-crank and blue-sky projects, and the importance of backup projects, communications, high expectations and perseverance.
Sometimes you have to look at the whole picture, big and small.
Sarah Cork, PhD
That was the lesson that emerged from Winship Cancer Institute researcher Erwin Van Meir’s laboratory, highlighted in a recent paper in Oncogene. Van Meir’s team has been studying vasculostatin, a secreted protein that inhibits blood vessel growth by tumors (hence the name). Vasculostatin was discovered by Balveen Kaur, now at Ohio State, while she was in Van Meir’s lab.
Van Meir and his colleagues originally began studying vasculostatin because it is a product of a gene that brain tumors somehow silence or get rid of, and studying the obstacles our bodies throws in cancer’s way may be a good way to learn how to fight it via modern medicine. Eventually, it could form the basis for a treatment to prevent a tumor from attracting new blood vessels.
Vasculostatin is somewhat unique because it is a secreted fragment of a membrane-bound protein, called BAI1. BAI1 has an apparently separate function as an “engulfment receptor,” allowing the recognition and internalization of dying cells.
Most of the secreted vasculostatin is around 40 kilodaltons in size, not 120 as previously thought.
Graduate student Sarah Cork discovered that most of the vasculostatin protein being produced by cells is actually much smaller than what had been originally discovered. She and Van Meir were surprised to find that the smaller, cleaved form of the protein still has potent anti-angiogenic activity.
The researchers were using a technique where a mixture of proteins is separated within a gel by electric current, transferred to a polymer sheet, and probed with antibodies. The large proteins appear at the top and the small proteins at the bottom.
“Previously, we had been running the gels for a long time to detect largeÂ protein fragments, so missed out on what was happening with smallÂ fragments which run off the gel,” Van Meir says. “We were only looking at the top of the
gel, when the smaller form of vasculostatin was actually much more
abundant as you can see on the picture of a gel run for a shorter time.”
More broadly, Van Meir says that the finding adds to understanding about BAI1’s dual function in the brain and how vasculostatin (big or small) might be used in anticancer therapy.
Over the last few years, pathologist Keqiang Ye and his colleagues have displayed an uncanny talent for finding potentially useful medicinal compounds. Recently another example of this talent appeared in Journal of Biological Chemistry.
Qi and Ye were looking for compounds that could inhibit the growth of an especially aggressive form of brain cancer, glioblastoma with deletion in the tumor suppressor gene PTEN. Tumors with this deletion do not respond to currently available targeted therapies.
The researchers found that acridine yellow G, a fluorescent dye used to stain microscope slides, can inhibit the growth of this tumor:
Oral administration of this compound evidently decreases the tumor volumes in both subcutaneous and intracranial models and elongates the life span of brain tumor inoculated nude mice. It also displays potent antitumor effect against human lung cancers. Moreover, it significantly decreases cell proliferation and enhances apoptosis in tumors…
Optimization of this compound by improving its potency through medicinal chemistry modification might warrant a novel anticancer drug for malignant human cancers.
Ye’s team observed that acridine yellow G appears not to be toxic in rodents. However, the acridine family of compounds tends to intercalate (insert itself) into DNA and can promote DNA damage, so more toxicology studies are needed. Other acridine family compounds such as quinacrine have been used to treat bacterial infections and as antiinflammatory agents, they note.
A paramecium stained with acridine orange, which shows anticancer activity for tumors containing PTEN mutations
Cancer cells have an array of built-in self-destruct buttons called death receptors. A drug that targets death receptors sounds like a promising concept, and death receptor-targeting drugs have been under development by several biotech companies. Unfortunately, soÂ far results in clinical trials have been disappointing, because cancer cells appear to develop resistance pathways.
Death receptor-targeting drugs under development include: drozitumab, mapatumumab, lexatumumab, AMG655, dulanermin.
Winship Cancer Institute researcher Shi-Yong Sun, PhD and colleagues have a paper in Journal of Biological ChemistryÂ that may help pick the tumors that are most likely to be vulnerable to death receptor-targeting drugs. This could help clinical researchersÂ identify potential successes ahead of time and maximize chances of a good response for patients.
Postdoctoral fellow Youtake Oh is the first author. Winship deputy director Fadlo Khuri, MD and Taofeek Owonikoko, MD, PhD, co-chair of Winship’s clinical and translational research committee, are co-authors. Khuri’s 2010 presentation on death receptor drugs and lung cancer is available here (PDF).
Sun’s team shows that mutations in the cancer-driving genes Ras and B-Raf both induce cancer cells to make more of one of the death receptors (death receptor 5). In addition, they show that cancer cells with mutations in Ras or B-Raf tend to be more vulnerable to drugs that target death receptor 5.
Shi-Yong Sun, PhD
These mutations are known to be more common in some types of cancer. For example, roughly half of melanomas have mutations in B-Raf.Â Vemurafenib, a drug that inhibits mutated B-Raf, was approved in August 2011 for the treatment of melanoma. K-ras mutations are similarly abundant in lung cancer.
The selection and targeting of tumors via their specific mutations is a growing trend. Sun says lung, colon and pancreatic cancer are all cancer types where Ras and Raf mutations are common enough to become useful biomarkers. In lung cancer, Sunâ€™s teamâ€™s results could be especially welcome news because, as a 2009 review concluded:
Recent studies indicate that patients with mutant KRAS tumors fail to benefit from adjuvant chemotherapy, and their disease does not respond to EGFR inhibitors. There is a dire need for therapies specifically for patients with KRAS mutant NSCLC.
This week, breast cancer researchers have been reporting encouraging clinical trial results with the drug everolimus at the San Antonio Breast Cancer Symposium. Everolimus is a mTOR inhibitor, first approved by the FDA for treatment of kidney cancer and then for post-transplant control of the immune system.
Ruth O’Regan, MD, director of the Translational Breast Cancer Research Program at Winship Cancer Institute, has led clinical studies of everolimusÂ in breast cancerÂ and has championed the strategy of combining mTOR inhibitors with current treatments for breast cancer.
She views the combination therapy as a potential alternative to chemotherapy for treating ER-positive advanced breast cancer when hormonal therapies have stopped working.
When resistance to hormonal therapies occurs, Dr. O’Regan explained, additional signaling pathways become activated. Unlike chemotherapy, which targets rapidly dividing cells, mTOR inhibitors are an example of the kind of treatment that may block growth-promoting signaling pathways.
Currently, Winship researchers are examining a combination involving everolimus and the EGFR inhibitor lapatinib for “triple-negative” breast cancer, a particularly aggressive and difficult-to-treat variety.