Possible answer to chemo pain in a multiple sclerosis drug

Investigators discover pain pathway and potential way to block it.

In a recently published study in the Journal of Biological Chemistry, Saint Louis University professor of pharmacological and physiological sciences Daniela Salvemini, Ph.D. describes two discoveries: a molecular pathway by which a painful chemotherapy side effect happens and a drug that may be able to stop it.

The chemotherapy drug paclitaxel is widely used to treat many forms of cancer, including breast, ovarian and lung cancers,” said Salvemini. “Though it is highly effective, the medication, like many other chemotherapy drugs, frequently is accompanied by a debilitating side effect called chemotherapy induced peripheral neuropathy, or CIPN.”

CIPN can appear as tingling or numbness in the hands and feet, shooting or burning pain in the limbs, or can feel like hot or cold temperature extremes. Symptoms may resolve within weeks or months of stopping the chemotherapy treatment or may last for years. In addition to causing patients suffering, CIPN is often a limiting factor when it comes to treatment.

Physicians estimate that CIPN can occur in 30 to 90 percent of patients treated with taxanes (the class of drugs that includes paclitaxel) and combination chemotherapies.

Salvemini and her colleagues studied paclitaxel, which also is known as Taxol, and discovered that the pain pathway (the series of interactions between molecular-level components) is dependent on activation of sphingosine 1-phosphate receptor subtype 1 (S1PR1) in the central nervous system by engaging a series of damaging neuro-inflammatory processes leading to pain. By inhibiting this molecule, they found that they could block and reverse paclitaxel-induced neuropathic pain without interfering with the drug’s anticancer effects.

This finding is particularly encouraging because a drug that modulates S1PR1 is already on the market. A medication called FTY720 (Gilenya) is FDA-approved as a therapy for multiple sclerosis. When Salvemini tested this drug in her lab, she found that the S1PR1 modulator weakened the neuroinflammatory processes, which in turn blocked and reversed neuropathic pain without altering the anticancer properties of paclitaxel. Further, the beneficial effects of FTY720 were not restricted to paclitaxel but also extended to another chemotherapeutic agent, the platinum based drug oxaliplatin which is widely used for metastatic colon cancer and other gastrointestinal cancers.

While clinical trials will be necessary to determine the safety and efficacy of the drug in treating CIPN, researchers are hopeful that they may be able not only to relieve cancer patients of debilitating pain, but also save more lives by permitting the administration of larger, potentially more effective doses of chemotherapy drugs.

We have identified a critical pathway by which CIPN develops and continues that can be targeted with a drug that is already FDA approved. This does not happen often,” said Salvemini. “We need to capitalize on these findings and explore use of these agents in cancer pain patients to improve quality of life and potentially maximize anticancer efficacy as soon as possible.”

Janes et al., (2014). The Development and Maintenance of Paclitaxel-Induced Neuropathic Pain Requires Activation of the Sphingosine 1-Phosphate Receptor Subtype 1. J. Biol. Chem., EPub Ahead of Print,  doi: 10.1074/jbc.M114.569574 [pdf]

Advertisements

Family dysfunction – a strong predictor of emotional problems in children of cancer patients

A cancer diagnosis affects the whole family, and a significant number of children of cancer patients may be at risk for emotional and behavioral problems. 

A new analysis published early online in CANCER, a peer-reviewed journal of the American Cancer Society, suggests that family dysfunction may increase a child’s risk of experiencing such problems after learning of a parent’s illness.

Approximately 21% of all newly diagnosed cancer patients are between the ages of 25 and 54 years, and many may have dependent children living with them at home. While most children and adolescents cope well with a parent’s illness, some can become highly distressed or develop psychosocial issues. Therefore, it is important to know which factors may affect a children’s adjustment to a parent’s cancer diagnosis and to develop specific screening tools and healthcare programs for children who may go on to experience problems.

In a recent study led by Birgit Möller, PhD, of the University Medical Center Hamburg-Eppendorf and the University Medical Center Münster in Germany, 235 families—including 402 parents and 324 children aged 11 to 21 years—completed questionnaires that assessed emotional and behavioral health. At least one parent in each family was diagnosed with cancer.

The researchers found that, compared with norms, children of cancer patients showed increased average levels of emotional and behavioural symptoms. From both the parents’ and the children’s perspectives, the best predictor of emotional and behavioral problems was general family dysfunction. “This means that in view of a life-threatening disease in a parent, the level of family functioning predicts children’s behavioral and emotional symptoms more than any other tested variable including illness-related factors,” Dr. Möller explained.

Dr. Möller noted that screening for child mental health problems, family dysfunction, and parental depression can be easily adopted into cancer care so that families in need of support can be identified. “Additional training of oncologists, interdisciplinary approaches, and family-based mental health liaison services are recommended to meet the needs of minor children and their families and to minimize negative long-term effects in children,” she said.

Dr. Möller and her team have developed a preventive counselling program—called the Children of Somatically Ill Parents (COSIP) program—that focuses on family communication, affective involvement of family members, flexible problem solving, mutual support, and parenting issues.

Möller et al., (2014). Children of cancer patients: Prevalence and predictors of emotional and behavioral problems. Cancer, EPub Ahead of Print, DOI: 10.1002/cncr.28644 [Abstract]

Study sheds light on racial disparity in colon cancer

African-Americans half as likely to have genetic marker linked to better survival

African-Americans with colon cancer are half as likely as Caucasian patients to have a type of colon cancer that is linked to better outcomes. The finding may provide insight into why African-Americans are more likely to die of colon cancer than Caucasians with the same stage of disease.

The population-based study of 503 people with colon cancer found that 14 percent of Caucasians and 7 percent of African-Americans had a genetic marker called microsatellite instability, or MSI. These types of tumors are known to be resistant to the chemotherapy drug 5FU. Yet, even without chemotherapy, these patients tend to have better outcomes.

We know that patients with MSI colon cancer do better without chemotherapy. But these improved survival benefits are limited among African-Americans with colon cancer,” says lead study author John M. Carethers, M.D., John G. Searle Professor and Chair of internal medicine at the University of Michigan Medical School.

Results of the study appear in the journal PLOS ONE.

The researchers identified patients through the North Carolina Colon Cancer Study, a population-based, case-control study conducted throughout central and eastern North Carolina. The North Carolina study includes both rural and urban areas, creating adequate representation by African-American and rural residents.

The group of patients Carethers and his colleagues looked at was 45 percent African-American and 55 percent Caucasian. Researchers examined tissue samples taken at the time of surgery and assessed it for various markers, including MSI.

In addition to the racial imbalance in MSI, the researchers also found that African-Americans patients were more likely than Caucasian patients to have cancer on the right side of their colon. This is significant because right-sided colon cancer is easier to miss with screening and more likely to be found larger or more advanced than left-sided cancers.

Right-sided colon cancer may be the ‘black ice’ of the colon – unseen but potentially deadly. Strategies to better recognize and detect right-sided cancer may need to be pursued in a broader fashion,” Carethers says.

Carethers et al., (2014) Influence of Race on Microsatellite Instability and CD8+ T Cell Infiltration in Colon Cancer. PLoS ONE, 9(6): e100461. doi:10.1371/journal.pone.0100461 [Article]

Gut bacteria may predict survival after stem cell transplant

Research demonstrates association between diversity of gut bacteria and survival.

New research, published online today in Blood, the Journal of the American Society of Hematology, suggests that the diversity of bacteria in the gastrointestinal tract of patients receiving stem cell transplants may be an important predictor of their post-transplant survival.

A healthy gastrointestinal tract contains a balanced community of microorganisms (known as microbiota), largely comprised of “friendly” bacteria that aid digestion and are important to immune system function. When this community of microbes is compromised, the microbiota may become less diverse, and the body becomes more susceptible to certain diseases.

Previous studies have shown that the intensive treatment given to individuals receiving a stem cell transplant from a healthy donor (known as an allogeneic stem cell transplant or SCT) can destroy a significant portion of the recipients’ gut microbiota and reduce its overall diversity. Disturbances of the gut microbiota have been shown to be correlated with post-transplant complications such as bloodstream infections and graft-versus-host disease.

While the link between gut microbiota and complications in allogeneic SCT has been previously established, until this point it has remained unclear whether the gut bacteria of transplant recipients could predict their survival,” said senior study author Ying Taur, MD, MPH, of the Lucille Castori Center for Microbes, Inflammation, and Cancer at Memorial Sloan Kettering Cancer Center. “This study sought to further explore the potential connection between transplantation, gut bacteria, and overall survival.

To better understand the association between post-transplant microbiota and patient outcomes, Dr. Taur and a team of researchers collected fecal specimens from 80 patients undergoing allogeneic SCT and sequenced each sample’s bacterial DNA. Specimens were collected within seven days of engraftment, the point at which transplanted blood-forming cells start to grow and make healthy cells in the recipient and the point at which researchers speculated that microbiota diversity would be greatest following pre-transplant conditioning.

Researchers compared patient outcomes based on diversity of microbiota in their specimens, grouping subjects into high, intermediate, and low microbiota diversity categories. At time of stem cell engraftment, 34 patients (42.5%) were observed to have low gut microbiota diversity, 20 (25%) of patients had intermediate diversity, and 26 (32.5%) patients had high diversity. The analysis continued for up to three years or until death or last follow-up.

Following their analyses, researchers found a strong connection between post-transplant gut microbiota diversity and outcomes, observing overall survival rates of 36 percent, 60 percent, and 67 percent among the low, intermediate, and high diversity groups, respectively. Furthermore, researchers observed that diversity was particularly associated with transplant-related outcomes, concluding that patients with low microbiota diversity were approximately five times more likely to die of transplant-related causes within the follow-up period than those with more diverse gut bacteria.

These results further underscore the significance of the gut microbiota in allogeneic stem cell transplant. A major question is whether we can improve outcomes by preserving diversity within the gut microbiota,”said Dr. Taur. “One possible strategy is to find ways to perform transplants in a manner that minimizes damage to the gut microbiota. Another approach would be to replenish the gut with beneficial microbes that are lost after this procedure is performed. We hope that this study will inspire additional research that will further examine the role and importance of the gut microbiota to stem cell transplant outcome.

Taur et al., (2014). The effects of intestinal tract bacterial diversity on mortality following allogeneic hematopoietic stem cell transplantation. Blood, EPub Ahead of Print, DOI:http://dx.doi.org/10.1182/blood-2014-02-554725 [Abstract]

Study compares survival for treatments of uncommon eye cancer

In patients with advanced uveal melanoma, treatment with the agent selumetinib, compared with chemotherapy, resulted in an improved cancer progression-free survival time and tumor response rate, but no improvement in overall survival, according to a study in the June 18 issue of JAMA. The modest improvement in clinical outcomes was accompanied by a high rate of adverse events.

Uveal melanoma arises from melanocytes within the choroid layer of the eye. There are about 1,500 new cases of uveal melanoma per year in the U.S., which is biologically distinct from skin related melanoma. Selumetinib is an oral agent that may help to inhibit the growth of cancer cells by blocking MEK1/2. A subgroup analysis from an earlier trial that included 20 patients with uveal melanoma suggested favorable results with selumetinib treatment, according to background information in the article.

Richard D. Carvajal, M.D., of Memorial Sloan-Kettering Cancer Center, New York, and colleagues randomly assigned patients with metastatic uveal melanoma to receive selumetinib (n = 50; orally twice daily), or chemotherapy (n = 51; temozolomide, orally daily for 5 of every 28 days, or dacarbazine, intravenously every 21 days) until disease progression, death, intolerable adverse effects, or withdrawal of consent. After analysis of the primary outcome, 19 additional patients were registered and 18 treated with selumetinib without randomization, to complete the planned 120-patient enrollment. 1The researchers reported that the median progression-free survival time was 7 weeks in the chemotherapy group (median treatment duration, 8 weeks) and 15.9 weeks in the selumetinib group (median treatment duration, 16.1 weeks). The 4-month progression-free survival rate was 8.5 percent with chemotherapy, and 43.1 percent with selumetinib. Median overall survival time was 9.1 months with chemotherapy and 11.8 months with selumetinib, a difference that was not statistically significant.

Tumor regression was uncommon with chemotherapy, whereas 49 percent of patients randomized to selumetinib achieved tumor regression. Treatment-related adverse events were observed in 97 percent of patients treated with selumetinib, with 37 percent requiring at least 1 dose reduction.

“In this hypothesis-generating study of patients with advanced uveal melanoma, selumetinib compared with chemotherapy resulted in a modestly improved progression-free survival time and rate of response; however, no improvement in overall survival was observed. Improvement in clinical outcomes was accompanied by a high rate of adverse events.” the authors conclude.

Carvajal et al., (2014). Effect of selumetinib vs chemotherapy on progression-free survival in uveal melanoma: A randomized clinical trial. JAMA., 311(23):2397-2405. doi:10.1001/jama.2014.6096 [Abstract]

Wishing for a miracle: New tool to help medical staff say ‘amen’

Cancer clinicians and a chaplain at the Johns Hopkins Kimmel Cancer Center have developed a tool to help doctors, nurses and other health care providers talk to dying patients and families who are, literally, praying for a miracle.

The AMEN (Affirm, Meet, Educate, No matter what) protocol, a script that can be used by medical staff, offers a way to negotiate these challenging conversations to affirm or acknowledge a patient’s hope, share the patient’s wish with others, continue to educate the patient and family about medical issues, and assure them that their health care team will remain with them throughout the duration of their care, “no matter what.”

The AMEN tool allows the provider to join the patient or family member as a fellow human being with hopes and aspirations, and fosters a sense of trust and commitment to care,” said Rhonda S. Cooper, M. Div., B.C.C., the Cancer Center’s chaplain.

In lectures at Johns Hopkins, she says, the tool has been presented to clinical staff as a way “to respect our patients’ beliefs and values as we care for them to the best of our ability.” Cooper and her colleagues described the conversational protocol online in the May 6 issue of the Journal of Oncology Practice.

According to Cooper, patients and their families often turn to the idea of a miracle during a serious illness or trauma. In a study cited by the researchers and conducted by the University of Connecticut and Georgetown University, 57 percent of adults randomly surveyed said they believed that “God’s intervention could save a family member” even when physicians said that any further treatments would be futile.

Doctors and nurses may feel uncomfortable discussing miracles as a religious event, or feel that they do not have the training or time to talk about miracles, Cooper says, but adds it is important not to dismiss the idea when patients or family bring it up.

If the provider makes a comment that sounds dismissive of God or the person’s faith or beliefs, that definitely will affect the trust relationship,” she says. “The goal of the conversation between provider and the patient or family is to stay connected, not debate the possibility of miracles happening or not happening.”

The AMEN tool, which specifically consists of a recommended script for talking with patients, can help medical experts see the hope for a miracle as an opportunity to join the patient or family in their end-of-life conversation, Cooper says. The goal is to maintain trust and foster open and honest communication as the care plan is being discussed. The tool can remind providers to “ask, rather than assume, what patients in treatment are hoping for,” said Anna Ferguson, RN, a collaborator on the protocol.

The “no matter what” aspect can be especially important for patients transitioning from aggressive to palliative care, Cooper noted. “We all believe that ‘non-abandonment’ or accompanying the patient or family ‘every step of the way’ regardless of treatment outcome is what we can assure everyone who steps through our doors.”

We do not expect providers to become theologians or ‘miracle experts,'” she stressed, “but instead to maintain the connection and respond to the patient’s invitation to journey with them through their experience.”

Cooper et al., (2014). AMEN in challenging conversations: Bridging the gaps between faith, hope, and medicine. J. Oncol. Prac., EPub Ahead of Print, doi: 10.1200/JOP.2014.001375 [Abstract]

African-American women more likely to be diagnosed with higher risk breast cancer

A research study led by cancer specialists at MedStar Washington Hospital Center found that African-American women frequently present with biologically less favorable subtypes of breast cancer.

Researchers at the Hospital Center’s Washington Cancer Institute analyzed the biology of breast cancer in 100 African-American women, using a method of genomic profiling. These genomic tests look at the expression of genes associated with the risk of recurrence in the population and further characterizes the biology of the tumor. The 70-gene MammaPrint test was used to determine the likelihood of a cancer recurrence. Out of the 100 patients, 66 women in the study were found to be high risk, meaning that their tumors had a higher risk of recurrence.

A companion BluePrint test was used to define the specific molecular subtype of each cancer. When classified by both genomic tests, African- American women with stage I to III breast cancer often presented with gene expression subtypes that were less favorable. The co-author of the research, Raquel Nunes, MD, a medical oncologist at the Washington Cancer Institute, presented the data as a scientific poster at the recent American Society of Clinical Oncology annual meeting.

It’s important that research continues to address these issues comprehensively, from the biology of the disease to the development of optimal treatment and access to healthcare.” said Dr. Nunes. “This work is particularly meaningful for us because it complements our interest in health disparities and highlights the enthusiastic participation of African-Americans in breast cancer research.”

Unlike genetic tests such as those for BRCA genes (which are inherited and look at overall susceptibility for developing breast cancer), genomic tests look at the genes inside a breast cancer cell and how strongly they are expressed. The findings support prior research that has looked at the biologic characteristics of breast cancer in African-American women, but this specific methodology reported here was used for the first time in this population.

Cancer specialists will continue to follow the patients in the research study over the next five years to evaluate their survival with treatment, according to their gene profile.

Additional Information:

Nunes et al., Genomic profiling of breast cancer in African-American women [poster]

American Society of Clinical Oncology 50th annual meeting 2014, Chicago, Illinois