Archive for the ‘Infertility’ Category

Newest precision medicine tool: Prostate cancer organoids

The researchers, whose results were published today in Cell, successfully grew six prostate cancer organoids from biopsies of patients with metastatic prostate cancer and a seventh organoid from a patient’s circulating tumor cells. Organoids are three-dimensional structures composed of cells that are grouped together and spatially organized like an organ. The histology, or tissue structure, of the prostate cancer organoids is highly similar to the metastasis sample from which they came. Sequencing of the metastasis samples and the matched organoids showed that each organoid is genetically identical to the patient’s cancer from which it originated.

“Identifying the molecular biomarkers that indicate whether a drug will work or why a drug stops working is paramount for the precision treatment of cancer,” said Yu Chen, MD, PhD, Assistant Attending Physician in the Genitourinary Oncology Service and Human Oncology and Pathogenesis Program at MSK. “But we are limited in our capacity to test drugs — especially in the prostate cancer setting, where only a handful of prostate cancer cell lines are available to researchers.”

With the addition of the seven prostate cancer organoids described in the Cell paper, Dr. Chen’s team has effectively doubled the number of existing prostate cancer cell lines.

“We now have a new resource at our disposal that captures the molecular diversity of prostate cancer. This will be an invaluable tool we can use to test drug sensitivity,” he added.

The use of organoids in studying cancer is relatively new, but the field is exploding quickly according to Dr. Chen. In 2009, Hans Clevers, MD, PhD, of the Hubrecht Institute in the Netherlands demonstrated that intestinal stem cells could form organoids. Dr. Clevers is the lead author on a companion piece also published in Cell today that describes how to create healthy prostate organoids. Dr. Chen’s paper is the first to demonstrate that organoids can be grown from prostate cancer samples.

The prostate cancer organoids can be used to test multiple drugs simultaneously, and Dr. Chen’s team is already retrospectively comparing the drugs given to each patient against the organoids for clues about why the patient did or didn’t respond to therapy. In the future, it’s possible that drugs could be tested on a patient’s organoid before being given to the patient to truly personalize treatment.

After skin cancer, prostate cancer is the most common cancer in American men — about 233,000 new cases will be diagnosed in 2014. It is also the second leading cause of cancer death in men; 1 in 36 men will die of the disease.

Despite its prevalence, prostate cancer has been difficult to replicate in the lab. Many mutations that play a role in its growth are not represented in the cell lines currently available. Cell lines can also differ from their original source, and because they are composed of single cells, they do not offer the robust information that an organoid — which more closely resembles a living organ — can provide.

source : http://www.sciencedaily.com/releases/2014/09/140904131142.htm

Study identifies gene network behind untreatable leukemia, possible treatment target

Scientists from the Cancer and Blood Diseases Institute (CBDI) at Cincinnati Children’s Hospital Medical Center report their results in a study posted online Sept. 4 by Cell Reports.

The specific forms of AML and MDS in the current study involve deletions on the arm of a specific chromosome in blood cells (del(5q). In patients with less aggressive forms of del(5q) MDS, the percentage of bone marrow blasts in their blood (the earliest, most immature cells of the myeloid cell line) is less than 5 percent. This means treatment prognosis for those patients typically is good, according to the study’s lead investigator, Daniel Starczynowski PhD, a researcher in the division of Experimental Hematology and Cancer Biology, part of the CBDI at Cincinnati Children’s.

“Unfortunately, a large portion of del(5q) AML and MDS patients have increased number of bone marrow blasts and additional chromosomal mutations,” Starczynowski said. “These patients have very poor prognosis because the disease is very resistant to available treatments such as chemotherapy and radiation. Finding new therapies is important and this study identifies new therapeutic possibilities.”

The researchers conducted their study in human AML/MDS cells and mouse models of del(5q) AML/MDS. They found that reduced expression of a certain gene in blood cells (miR-146a) led to activation of a molecular signaling network involving several components of NF-kB, one of which involved a protein called p62 — a critical regulator of cell metabolism, cellular remodeling and certain cancers.

Deletion of the miR-146a gene led to overexpression of p62, which caused sustained activation of what researchers identified as an NF-kB signaling network. This fueled the survival and aggressive growth of leukemic cells in cells and in mouse models.

Earlier attempts in previous studies to directly inhibit NF-kB (a key molecular facilitator to the leukemic process) have not proven successful, according to investigators on the current paper. So the authors performed follow-up laboratory tests to look for possible vulnerabilities to NF-kB and a potential workaround by targeting instead p62 within the NF-kB signaling network.

The researcher next tested inhibiting/knocking down p62 as an experimental treatment strategy in mouse models of leukemia and in human cells. The authors reported that targeting p62 prevented expansion of leukemic cells in mouse models and reduced the number of leukemia cell colonies by 80 percent in human AML/MDS cells.

Starczynowski stressed that significant additional research is needed to further verify the findings and learn more about the molecular processes involved. He also cautioned that laboratory results in mouse models do not necessarily translate to humans, and it isn’t known at this time how the findings might be directly applicable to clinical treatment.

source : http://www.sciencedaily.com/releases/2014/09/140904131603.htm

Rare stem cells hold potential for infertility treatments

Researchers studying infertility in mouse models found that, unlike similar types of cells that develop into sperm, the stem cells that express PAX7 can survive treatment with toxic drugs and radiation. If the findings hold true in people, they eventually could lead to new strategies to restore or protect fertility in men undergoing cancer treatment.

“Unfortunately, many cancer treatments negatively impact fertility, and men who receive such treatments are at high risk of losing their fertility. This is of great concern among cancer patients,” said Dr. Diego H. Castrillon, Associate Professor of Pathology and Director of Investigative Pathology. “The PAX7 stem cells we identified proved highly resistant to cancer treatments, suggesting that they may be the cells responsible for the recovery of fertility following such treatments.”

Infertility, which the Centers for Disease Control estimates affects as many as 4.7 million men in the United States, is a key complication of cancer treatments, such as chemotherapy and radiation therapy.

The new findings, presented in the Journal of Clinical Investigation, provide valuable insight into the process of sperm development. Known as spermatogenesis, sperm development is driven by a population of “immature” stem cells called progenitors in the testes. These cells gradually “mature” into fully differentiated sperm cells. Dr. Castrillon and his team tracked progenitor cells that express the protein PAX7 in mouse testes, and found that these cells gradually give rise to mature sperm.

“We have long known that male fertility is driven by rare stem cells within the testes, but the precise identity of these stem cells has been disputed,” said Dr. Castrillon, who holds the John H. Childers, M.D. Professorship in Pathology. “Our findings suggest that these rare PAX7 cells are the key cells within the testes that are ultimately responsible for male fertility.”

Importantly, even after exposure to toxic chemotherapy or radiation treatments, the PAX7-expressing cells continued to divide and thus could contribute to restoring sperm development.

source : http://www.sciencedaily.com/releases/2014/09/140904153805.htm