COLUMBUS, Ohio – Researchers have identified a self-feeding “vicious circle” of molecules that keeps acute leukemia cells alive and growing and that drives the disease forward.

The findings suggest a new strategy for treating acute myeloid leukemia (AML), one that targets this molecular network and lowers the amount of a protein called KIT, say researchers at the Ohio State University Comprehensive Cancer Center-Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC-James) who conducted the study.

Published in the April 13 issue of the journal Cancer Cell, the study described a new network of protein and microRNA molecules that, when imbalanced, contributes to abnormal KIT protein abundance and favors leukemia development. The researchers were also able to target this network with therapeutic drugs.

“We now understand the mechanism responsible for making so much KIT protein in AML cells, and we believe that targeting that mechanism and reducing the amount of that protein will prove to be a more effective therapy for this disease than the current standard of care,” says study leader Dr. Guido Marcucci, professor of internal medicine and an AML specialist at the OSUCCC-James.

AML strikes 12,800 Americans, killing 9,000 of them each year. More than 80 percent of those cases have elevated levels of KIT protein.

Currently, doctors treat AML using standard chemotherapy. Drugs that target and block the activity of the KIT protein are being tested in clinical trials. These agents, called tyrosine kinase inhibitors, bind to the protein and stop disease progression, but they can lose their effectiveness when new mutations that arise during the course of the disease alter the protein.

“Our study suggests that the amount of KIT protein in cancer cells is as important as its activity, and we discovered that the amount of the protein is controlled by a circular network of molecules that has many points of entry,” says senior co-leader Dr. Ramiro Garzon, assistant professor of internal medicine and an AML specialist at the OSUCCC-James.

“These findings provide a strong rationale for the use and development of drugs that target the components of this network rather than focusing on the activity of KIT alone.”

Marcucci, Garzon, first author Shujun Liu, assistant professor of internal medicine, and their colleagues began this study by showing that patients with mutations in the KIT gene in their leukemic cells had the highest levels of the KIT protein in those cells, and that these patients also had the poorest survival.

“This told us that the amount of the protein in cancer cells is important to the disease process,” Liu says.

Using laboratory-grown AML cells, the researchers identified the series of molecules that control the amount of KIT protein, showing for the first time that a microRNA called miR-29b, along with several well-known cancer-related genes, regulate KIT production.

Normally, these elements work in a balanced fashion to produce the correct amount of KIT protein for healthy cell survival and proliferation. That normal balance is derailed when gene mutations or other genetic damage occurs in the network and promotes the overproduction of the KIT protein.

“It becomes a vicious circle because no matter where genetic damage occurs, the result is the same – over activation of the circle, over expression of the KIT protein, and proliferation of leukemic cells,” Liu says.

Using a mouse model, the researchers showed that raising the amount of mutated KIT protein causes leukemia, and drugs that target the network lower the amount of that protein and drive the leukemia into remission. These drugs included proteasome inhibitors, histone deacetylase inhibitors, along with inhibitors of molecules called NF?B and Sp1.

Funding from the National Cancer Institute, the Harry T. Mangurian Jr. Foundation Leukemia Research Fund, the Coleman Leukemia Research Foundation, the Sidney Kimmel Cancer Research Foundation, and the Deutsche Krebshilfe (Dr. Mildred Scheel Foundation for Cancer Research) supported this research.

Other Ohio State researchers involved in this study were Lai-Chu Wu, Jiuxia Pang, Ramasamy Santhanam, Sebastian Schwind, Yue-Zhong Wu, Christopher Hickey, Jianhua Yu, Heiko Becker, Kati Maharry, Michael D. Radmacher, Chenglong Li, Susan P. Whitman, Anjali Mishra, Nicole Stauffer, Anna M. Eiring, Roger Briesewitz, Robert A. Baiocchi, Kenneth K. Chan, Michael A. Caligiuri, John C. Byrd, Carlo M. Croce, Clara D. Bloomfield and Danilo Perrotti.

The Ohio State University Comprehensive Cancer Center- Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (http://cancer.osu.edu) is one of only 40 Comprehensive Cancer Centers in the United States designated by the National Cancer Institute. Ranked by U.S. News & World Report among the top 20 cancer hospitals in the nation, The James is the 180-bed adult patient-care component of the cancer program at The Ohio State University. The OSUCCC-James is one of only seven funded programs in the country approved by the NCI to conduct both Phase I and Phase II clinical trials. (source medicalcenter.osu.edu)

A Michiana man is asking for help from the public as he intensifies his search for a suitable bone marrow donor. Jeff Lafferty of Osceola is going to great lengths to beat the great odds he faces as a person of mixed race. On the ice, Jeff is known as “Coach” Lafferty who leads the Michiana Sting—a woman’s hockey team—into battle.

Off the ice, Jeff has been battling cancer for the past five years. “It’s a treatable form of Leukemia, which is Chronic Lymphocytic Leukemia,” he said. “In order for us to get it in remission would be the bone marrow transplant, that’s the only way I would be one hundred percent cancer free.”

The prospects would be easier if Jeff were 100-percent Caucasian. Of all the potential donors on the “Be the Match” Donor Registry, about 6 million people, or 74-percent of the total, are Caucasian. If Jeff were 100-percent Hispanic, he’d have 800-thousand potential donors waiting to help. But since Jeff is a mixture of both races, he has just 250-thousand chances to find a match through the registry. Mixed race donors make up just 3 percent of the total.

“As I looked into it, you know this became a growing problem with me being of mixed race having a Hispanic mother Caucasian father, it became a bigger issue then at that point. Knowing that there’s not a whole lot of mixed race people that are on the donor list,” Lafferty said.

It’s now Jeff’s goal to try and get more people, in general, and more people of mixed race, in particular, to sign up for the donor registry. Lafferty has organized a marrow donor drive for this Saturday in Mishawaka.

“With a growing Hispanic population here in the Michiana area, it’s a very big reason why I wanted to do this,” Lafferty said. “My goal is to save some body’s life, so if it means hopefully 40, 50 people show up, fantastic, if some body’s life is saved and only ten people who up, then that’s even better too.”

The marrow drive will take place March 27th from 10 a.m. until 4 p.m. at the Southside General Baptist Church in Mishawaka, 1615 S. Spring Street. The initial visit involves having your cheek swabbed. The process becomes more complicated if one becomes an actual donor. For more information visit: http://www.marrow.org/
A blood drive will also take place at the church from 10 a.m. until 1 p.m.

About Be The Match
Be The Match is a movement that engages a growing community of people inspired to help patients who need an unrelated marrow or umbilical cord blood transplant. The National Marrow Donor Program (NMDP), a leader in the field of marrow and cord blood transplantation, created Be The Match to provide opportunities for the public to become involved in saving the lives of people with leukemia, lymphoma and other life-threatening diseases. Volunteers can join the Be The Match Registry – the world’s largest and most diverse listing of potential marrow donors and donated cord blood units – as well as contribute financially to Be The Match Foundation or give their time. For more information, visit BeTheMatch.org or call 1 (800) MARROW-2

• What are bone marrow and hematopoietic stem cells?

Bone marrow is the soft, sponge-like material found inside bones. It contains immature cells known as hematopoietic or blood-forming stem cells. (Hematopoietic stem cells are different from embryonic stem cells. Embryonic stem cells can develop into every type of cell in the body.) Hematopoietic stem cells divide to form more blood-forming stem cells, or they mature into one of three types of blood cells: White blood cells, which fight infection; red blood cells, which carry oxygen; and platelets, which help the blood to clot. Most hematopoietic stem cells are found in the bone marrow, but some cells, called peripheral blood stem cells (PBSCs), are found in the bloodstream. Blood in the umbilical cord also contains hematopoietic stem cells. Cells from any of these sources can be used in transplants.

• What are bone marrow transplantation and peripheral blood stem cell transplantation?

Bone marrow transplantation (BMT) and peripheral blood stem cell transplantation (PBSCT) are procedures that restore stem cells that have been destroyed by high doses of chemotherapy and/or radiation therapy. There are three types of transplants:

* In autologous transplants, patients receive their own stem cells.
* In syngeneic transplants, patients receive stem cells from their identical twin.
* In allogeneic transplants, patients receive stem cells from their brother, sister, or
parent. A person who is not related to the patient (an unrelated donor) also may be used.

• Why are BMT and PBSCT used in cancer treatment?

One reason BMT and PBSCT are used in cancer treatment is to make it possible for patients to receive very high doses of chemotherapy and/or radiation therapy. To understand more about why BMT and PBSCT are used, it is helpful to understand how chemotherapy and radiation therapy work.

Chemotherapy and radiation therapy generally affect cells that divide rapidly. They are used to treat cancer because cancer cells divide more often than most healthy cells. However, because bone marrow cells also divide frequently, high-dose treatments can severely damage or destroy the patient’s bone marrow. Without healthy bone marrow, the patient is no longer able to make the blood cells needed to carry oxygen, fight infection, and prevent bleeding. BMT and PBSCT replace stem cells destroyed by treatment. The healthy, transplanted stem cells can restore the bone marrow’s ability to produce the blood cells the patient needs.

In some types of leukemia, the graft-versus-tumor (GVT) effect that occurs after allogeneic BMT and PBSCT is crucial to the effectiveness of the treatment. GVT occurs when white blood cells from the donor (the graft) identify the cancer cells that remain in the patient’s body after the chemotherapy and/or radiation therapy (the tumor) as foreign and attack them. (A potential complication of allogeneic transplants called graft-versus-host disease is discussed in Questions 5 and 14.)

• What types of cancer are treated with BMT and PBSCT?

BMT and PBSCT are most commonly used in the treatment of leukemia and lymphoma. They are most effective when the leukemia or lymphoma is in remission (the signs and symptoms of cancer have disappeared). BMT and PBSCT are also used to treat other cancers such as neuroblastoma (cancer that arises in immature nerve cells and affects mostly infants and children) and multiple myeloma. Researchers are evaluating BMT and PBSCT in clinical trials (research studies) for the treatment of various types of cancer.

• How are the donor’s stem cells matched to the patient’s stem cells in allogeneic or syngeneic transplantation?

To minimize potential side effects, doctors most often use transplanted stem cells that match the patient’s own stem cells as closely as possible. People have different sets of proteins, called human leukocyte-associated (HLA) antigens, on the surface of their cells. The set of proteins, called the HLA type, is identified by a special blood test.

In most cases, the success of allogeneic transplantation depends in part on how well the HLA antigens of the donor’s stem cells match those of the recipient’s stem cells. The higher the number of matching HLA antigens, the greater the chance that the patient’s body will accept the donor’s stem cells. In general, patients are less likely to develop a complication known as graft-versus-host disease (GVHD) if the stem cells of the donor and patient are closely matched. GVHD is further described in Question 14.

Close relatives, especially brothers and sisters, are more likely than unrelated people to be HLA-matched. However, only 25 to 35 percent of patients have an HLA-matched sibling. The chances of obtaining HLA-matched stem cells from an unrelated donor are slightly better, approximately 50 percent. Among unrelated donors, HLA-matching is greatly improved when the donor and recipient have the same ethnic and racial background. Although the number of donors is increasing overall, individuals from certain ethnic and racial groups still have a lower chance of finding a matching donor. Large volunteer donor registries can assist in finding an appropriate unrelated donor (see Question 19).

Because identical twins have the same genes, they have the same set of HLA antigens. As a result, the patient’s body will accept a transplant from an identical twin. However, identical twins represent a small number of all births, so syngeneic transplantation is rare.

• How is bone marrow obtained for transplantation?

The stem cells used in BMT come from the liquid center of the bone, called the marrow. In general, the procedure for obtaining bone marrow, which is called “harvesting,” is similar for all three types of BMTs (autologous, syngeneic, and allogeneic). The donor is given either general anesthesia, which puts the person to sleep during the procedure, or regional anesthesia, which causes loss of feeling below the waist. Needles are inserted through the skin over the pelvic (hip) bone or, in rare cases, the sternum (breastbone), and into the bone marrow to draw the marrow out of the bone. Harvesting the marrow takes about an hour.

The harvested bone marrow is then processed to remove blood and bone fragments. Harvested bone marrow can be combined with a preservative and frozen to keep the stem cells alive until they are needed. This technique is known as cryopreservation. Stem cells can be cryopreserved for many years.

• How are PBSCs obtained for transplantation?

The stem cells used in PBSCT come from the bloodstream. A process called apheresis or leukapheresis is used to obtain PBSCs for transplantation. For 4 or 5 days before apheresis, the donor may be given a medication to increase the number of stem cells released into the bloodstream. In apheresis, blood is removed through a large vein in the arm or a central venous catheter (a flexible tube that is placed in a large vein in the neck, chest, or groin area). The blood goes through a machine that removes the stem cells. The blood is then returned to the donor and the collected cells are stored. Apheresis typically takes 4 to 6 hours. The stem cells are then frozen until they are given to the recipient.

• How are umbilical cord stem cells obtained for transplantation?

Stem cells also may be retrieved from umbilical cord blood. For this to occur, the mother must contact a cord blood bank before the baby’s birth. The cord blood bank may request that she complete a questionnaire and give a small blood sample.

Cord blood banks may be public or commercial. Public cord blood banks accept donations of cord blood and may provide the donated stem cells to another matched individual in their network. In contrast, commercial cord blood banks will store the cord blood for the family, in case it is needed later for the child or another family member.

After the baby is born and the umbilical cord has been cut, blood is retrieved from the umbilical cord and placenta. This process poses minimal health risk to the mother or the child. If the mother agrees, the umbilical cord blood is processed and frozen for storage by the cord blood bank. Only a small amount of blood can be retrieved from the umbilical cord and placenta, so the collected stem cells are typically used for children or small adults.

• Are any risks associated with donating bone marrow?

Because only a small amount of bone marrow is removed, donating usually does not pose any significant problems for the donor. The most serious risk associated with donating bone marrow involves the use of anesthesia during the procedure.

The area where the bone marrow was taken out may feel stiff or sore for a few days, and the donor may feel tired. Within a few weeks, the donor’s body replaces the donated marrow; however, the time required for a donor to recover varies. Some people are back to their usual routine within 2 or 3 days, while others may take up to 3 to 4 weeks to fully recover their strength.

• Are any risks associated with donating PBSCs?

Apheresis usually causes minimal discomfort. During apheresis, the person may feel lightheadedness, chills, numbness around the lips, and cramping in the hands. Unlike bone marrow donation, PBSC donation does not require anesthesia. The medication that is given to stimulate the release of stem cells from the marrow into the bloodstream may cause bone and muscle aches, headaches, fatigue, nausea, vomiting, and/or difficulty sleeping. These side effects generally stop within 2 to 3 days of the last dose of the medication.

• How does the patient receive the stem cells during the transplant?

After being treated with high-dose anticancer drugs and/or radiation, the patient receives the stem cells through an intravenous (IV) line just like a blood transfusion. This part of the transplant takes 1 to 5 hours.

• Are any special measures taken when the cancer patient is also the donor (autologous transplant)?

The stem cells used for autologous transplantation must be relatively free of cancer cells. The harvested cells can sometimes be treated before transplantation in a process known as “purging” to get rid of cancer cells. This process can remove some cancer cells from the harvested cells and minimize the chance that cancer will come back. Because purging may damage some healthy stem cells, more cells are obtained from the patient before the transplant so that enough healthy stem cells will remain after purging.

• What happens after the stem cells have been transplanted to the patient?

After entering the bloodstream, the stem cells travel to the bone marrow, where they begin to produce new white blood cells, red blood cells, and platelets in a process known as “engraftment.” Engraftment usually occurs within about 2 to 4 weeks after transplantation. Doctors monitor it by checking blood counts on a frequent basis. Complete recovery of immune function takes much longer, however—up to several months for autologous transplant recipients and 1 to 2 years for patients receiving allogeneic or syngeneic transplants. Doctors evaluate the results of various blood tests to confirm that new blood cells are being produced and that the cancer has not returned. Bone marrow aspiration (the removal of a small sample of bone marrow through a needle for examination under a microscope) can also help doctors determine how well the new marrow is working.

• What are the possible side effects of BMT and PBSCT?

The major risk of both treatments is an increased susceptibility to infection and bleeding as a result of the high-dose cancer treatment. Doctors may give the patient antibiotics to prevent or treat infection. They may also give the patient transfusions of platelets to prevent bleeding and red blood cells to treat anemia. Patients who undergo BMT and PBSCT may experience short-term side effects such as nausea, vomiting, fatigue, loss of appetite, mouth sores, hair loss, and skin reactions.

Potential long-term risks include complications of the pretransplant chemotherapy and radiation therapy, such as infertility (the inability to produce children); cataracts (clouding of the lens of the eye, which causes loss of vision); secondary (new) cancers; and damage to the liver, kidneys, lungs, and/or heart.

With allogeneic transplants, a complication known as graft-versus-host disease (GVHD) sometimes develops. GVHD occurs when white blood cells from the donor (the graft) identify cells in the patient’s body (the host) as foreign and attack them. The most commonly damaged organs are the skin, liver, and intestines. This complication can develop within a few weeks of the transplant (acute GVHD) or much later (chronic GVHD). To prevent this complication, the patient may receive medications that suppress the immune system. Additionally, the donated stem cells can be treated to remove the white blood cells that cause GVHD in a process called “T-cell depletion.” If GVHD develops, it can be very serious and is treated with steroids or other immunosuppressive agents. GVHD can be difficult to treat, but some studies suggest that patients with leukemia who develop GVHD are less likely to have the cancer come back. Clinical trials are being conducted to find ways to prevent and treat GVHD.

The likelihood and severity of complications are specific to the patient’s treatment and should be discussed with the patient’s doctor.

• What is a “mini-transplant”?

A “mini-transplant” (also called a non-myeloablative or reduced-intensity transplant) is a type of allogeneic transplant. This approach is being studied in clinical trials for the treatment of several types of cancer, including leukemia, lymphoma, multiple myeloma, and other cancers of the blood.

A mini-transplant uses lower, less toxic doses of chemotherapy and/or radiation to prepare the patient for an allogeneic transplant. The use of lower doses of anticancer drugs and radiation eliminates some, but not all, of the patient’s bone marrow. It also reduces the number of cancer cells and suppresses the patient’s immune system to prevent rejection of the transplant.

Unlike traditional BMT or PBSCT, cells from both the donor and the patient may exist in the patient’s body for some time after a mini-transplant. Once the cells from the donor begin to engraft, they may cause the graft-versus-tumor (GVT) effect and work to destroy the cancer cells that were not eliminated by the anticancer drugs and/or radiation. To boost the GVT effect, the patient may be given an injection of the donor’s white blood cells. This procedure is called a “donor lymphocyte infusion.”

• What is a “tandem transplant”?

A “tandem transplant” is a type of autologous transplant. This method is being studied in clinical trials for the treatment of several types of cancer, including multiple myeloma and germ cell cancer. During a tandem transplant, a patient receives two sequential courses of high-dose chemotherapy with stem cell transplant. Typically, the two courses are given several weeks to several months apart. Researchers hope that this method can prevent the cancer from recurring (coming back) at a later time.

• How do patients cover the cost of BMT or PBSCT?

Advances in treatment methods, including the use of PBSCT, have reduced the amount of time many patients must spend in the hospital by speeding recovery. This shorter recovery time has brought about a reduction in cost. However, because BMT and PBSCT are complicated technical procedures, they are very expensive. Many health insurance companies cover some of the costs of transplantation for certain types of cancer. Insurers may also cover a portion of the costs if special care is required when the patient returns home.

There are options for relieving the financial burden associated with BMT and PBSCT. A hospital social worker is a valuable resource in planning for these financial needs. Federal Government programs and local service organizations may also be able to help.

The National Cancer Institute’s (NCI) Cancer Information Service (CIS) can provide patients and their families with additional information about sources of financial assistance (see below).

• What are the costs of donating bone marrow, PBSCs, or umbilical cord blood?

Persons willing to donate bone marrow or PBSCs must have a sample of blood drawn to determine their HLA type. This blood test usually costs $65 to $96. The donor may be asked to pay for this blood test, or the donor center may cover part of the cost. Community groups and other organizations may also provide financial assistance. Once a donor is identified as a match for a patient, all of the costs pertaining to the retrieval of bone marrow or PBSCs is covered by the patient or the patient’s medical insurance.

A woman can donate her baby’s umbilical cord blood to public cord blood banks at no charge. However, commercial blood banks do charge varying fees to store umbilical cord blood for the private use of the patient or his or her family.

• Where can people get more information about potential donors and transplant centers?

The National Marrow Donor Program (NMDP), a federally funded nonprofit organization, was created to improve the effectiveness of the search for donors. The NMDP maintains an international registry of volunteers willing to be donors for all sources of blood stem cells used in transplantation: Bone marrow, peripheral blood, and umbilical cord blood.

The NMDP Web site contains a list of participating transplant centers at http://www.marrow.org/PATIENT/Plan_for_Tx/Choosing_a_TC/US_NMDP_Transplant_Centers/tc_list_by_state.pl

The list includes descriptions of the centers, as well as their transplant experience, survival statistics, research interests, pretransplant costs, and contact information.
Organization:     National Marrow Donor Program
Address:     Suite 100
3001 Broadway Street, NE.
Minneapolis, MN 55413–1753
Telephone     612–627–5800
1–800–627–7692 (1–800–MARROW–2)
1–888–999–6743 (Office of Patient Advocacy)
E-mail:     patientinfo@nmdp.org
Internet Web site:     http://www.marrow.org

• Where can people get more information about clinical trials of BMT and PBSCT?

Clinical trials that include BMT and PBSCT are a treatment option for some patients. Information about ongoing clinical trials is available from NCI’s Cancer Information Service (see below), or from the NCI’s Web site at http://www.cancer.gov/clinicaltrials

(source www.cancer.gov)

View and Download the Bone Marrow Transplantation Facts PDF

Current transplantation therapies rely on the infusion of donor stem cells into a patient’s bone marrow to generate new, healthy blood cells without disease. But that procedure is often risky and can result in fatal complications, due in part to “graft-versus-host disease,” in which transplanted cells react against foreign tissues of the recipient. One means of circumventing this immune rejection problem would be to generate hematopoietic stem cells, or HSCs, using the patient’s own precursor cells. Such cells would be perfectly genetically matched, but in order to generate such cells, scientists must first understand the molecular processes that underlie specification of HSCs.

“If we could generate healthy HSCs from patients and transplant them back into their own bone marrow, it would eliminate many complications,” said David Traver, who headed the research team.

“Our findings are an important step toward this goal because they provide a better understanding of how HSCs, the cell type responsible for the clinical benefits of bone marrow transplants, are first specified during development.

“This improved understanding will aid efforts to instruct pluripotent embryonic stem cells (ESCs), the stem cells that can produce all types of tissue-specific stem cells in the body, to make HSCs; something that is not currently possible. In other words, we are one step closer now to understanding how to clinically generate HSCs for cellular replacement therapies from ESCs,” he added.

Traver and his colleagues made their discoveries in zebrafish, a model laboratory organism for geneticists in which embryos are transparent, allowing the researchers to observe and track individual stem cells with a microscope.

“Using zebra-fish embryos with fluorescently labeled tissues, we were able to demonstrate that HSCs arise directly from cells lining the floor of the dorsal aorta by imaging the process in living embryos.”

The study appears in this week’s early online edition of the journal Nature. (Source-ANI RAS)

Gertrude Elion invented the leukemia-fighting drug 6-mercaptopurine and drugs that facilitated kidney transplants.

Gertrude Elion patented the leukemia-fighting drug 6-mercaptopurine in 1954 and has made a number of significant contributions to the medical field. Dr. Gertrude Elion’s research led to the development of Imuran, a drug that aids the body in accepting transplanted organs, and Zovirax, a drug used to fight herpes.

Including 6-mercaptopurine, Getrude Elion’s name is attached to some 45 patents. In 1988, she was awarded the Nobel Prize in Medicine with George Hitchings and Sir James Black. Dr. Gertrude Elion was inducted into the National Inventors Hall of Fame in 1991, she continued to be an advocate for medical and scientific advancement until her death in February of 1999.

The child of Lithuanian and Polish immigrants, Gertrude Elion decided to become involved in cancer research after losing her grandfather to cancer when she was 15 years old. At age 19, she graduated with the highest undergraduate honors in chemistry from Hunter College. However, 15 institutes rejected her application for graduate school because of the unfair discrimination towards women in the sciences that existed at that time. Elion was forced to work as an unpaid lab assistant in order to have the opportunity to further her research in science. In 1944, Burroughs Wellcome, a pharmaceuticals company, hired Gertrude Elion to work with nucleic acids. During her 39-year career there, Gertrude Elion made most of her scientific advances, including the development of 6-mercaplopurine used in chemotherapy to treat children with leukemia that won her the Nobel Prize.

Timeline:
1918 Born on January 23, in New York City, New York.

1933 Enters Hunter College at the age of 15.

1937 Graduates summa cum laude with a B.S. degree in Chemistry. There were few women working as chemists, and many labs refused to hire women at the time, so Gertrude earned a Masters of Science degree in Chemistry from New York University and taught high school

1944 Is hired by Burroughs-Wellcome and begins a 40 year scientific partnership with George Hitchings. Develops two drugs with Hitchings for the treatment of acute laukemia. Becomes the leader of a large team of scientists that discovers drugs for the treatment of gout and to relieve the side-effects of chemotherapy.

1963 Discovers a drug that makes kidney transplants between unrelated donors possible.

1967 Is named the head of the Department of Experimental Therapy. Develops the world’s first anti-viral medication that is often used for the treatment of herpes.

1983 Retires holding 45 patents. She remains active as a scientific advisor and consultant.

1991 Along with George Hitchings and Sr. James Black, wins the Nobel Prize for Medicine.

1991 Is inducted into the National Inventors Hall of Fame and is presented with the National Medal of Science.

1999 Dies in February, 1999.

cancer cell

Their discovery, published in the November 12 issue of Nature, lays the foundation for a new kind of therapy aimed directly at a critical human protein — one of a few thousand so-called transcription factors — that could someday be used to treat a variety of diseases, especially multiple types of cancer.

“There is a pressing need for drugs that target transcription factors, both for use as scientific tools in the laboratory and as therapies in the clinic,” said senior author James Bradner, a Harvard chemical biologist and oncologist at the Dana-Farber Cancer Institute and an associate member of the Broad Institute of MIT and Harvard. “Our work brings us a step closer toward that goal for a protein with major roles in cancer, cardiovascular disease and stem cell biology.”

If human physiology is like a puppet show, then transcription factors pull the puppet strings. They bind to DNA and turn genes on or off, setting in motion genetic cascades that control how normal cells grow and develop. They also help maintain tumor growth, underscoring their importance as cancer drug targets. Yet transcription factors are counted among the most difficult molecules to neutralize with a drug — in fact, no such drugs are currently available.

Based on his work as an oncologist, Bradner became deeply interested in a human protein called NOTCH. The gene encoding this protein is often damaged, or mutated, in patients with a form of blood cancer, known as T-ALL or T-cell acute lymphoblastic leukemia.

Abnormal NOTCH genes found in cancer patients remain in a state of constant activity, switched on all the time, which helps to drive the uncontrolled cell growth that fuels tumors. Similar abnormalities in NOTCH also underlie a variety of other cancers, including lung, ovarian, pancreatic and gastrointestinal cancers.

Even with this deep scientific knowledge, drugs against NOTCH — or any other transcription factor — have traditionally been extremely difficult, if not impossible, to develop. Most current drugs take the form of small chemicals (known as “small molecules”) or larger-sized proteins, both of which have proven impractical to date for disabling transcription factors.

A few years ago, Bradner and his colleagues hatched a different idea about how to tame the runaway NOTCH protein. Looking closely at its structure as well as the structures of its partner proteins, they noticed a key protein-to-protein junction that featured a helical shape.

“We figured if we could generate a set of tiny little helices we might be able to find one that would hit the sweet spot and shut down NOTCH function,” said Bradner.

Creating and testing these helices involved a team of interdisciplinary researchers, including Greg Verdine, Erving Professor of Chemistry at Harvard University and director of the Chemical Biology Initiative at Dana-Farber Cancer Institute, as well as scientists at Brigham and Women’s Hospital and the Broad Institute’s Chemical Biology Program, which is directed by Stuart Schreiber.

Verdine invented a drug discovery technology that uses chemical braces or “staples” to hold the shapes of different protein snippets. Without these braces, the snippets (called “peptides”) would flop around, losing their three-dimensional structure and thus their biological activity. Importantly, cells can readily absorb stapled peptides, which are significantly smaller than proteins. That means the peptides can get to the right locations inside cells to alter gene regulation.

“Stapled peptides promise to significantly expand the range of what’s considered ‘druggable,’” said Verdine, who is a co-senior author of the study and an associate member of the Broad Institute. “With our discovery, we’ve declared open season on transcription factors and other intractable drug targets.”

After designing and testing several synthetic stapled peptides, the research team identified one with remarkable activity. Not only could it bind to the right proteins and reach the right places inside cells, it also showed the desired biological effect: the ability to disrupt NOTCH function.

Moreover, experiments in cultured cells as well as in mice proved the peptide’s ability to limit the growth of cancer cells fueled exclusively by NOTCH. Interestingly, these effects are also seen at the level of gene activity or “expression.” The researchers looked at the expression levels of genes across the genome, in both cells and mice treated with the peptide, and observed markedly reduced expression of genes that are controlled directly and indirectly by NOTCH. These results offer some early insights into how the peptide works at a molecular level.

In addition to the potential therapeutic applications to NOTCH-dependent cancers, the Nature study also forms the basis of a general strategy for taking aim at other transcription factors. “A variety of key transcription factors assemble in a manner similar to NOTCH,” said first author Raymond Moellering, a graduate student in Harvard University’s Department of Chemistry and Chemical Biology who works with both Verdine and Bradner. “Our approach could offer a template for targeting many other master regulators in cancer.” www.medindia.net

NEW YORK – Genzyme Corp. must collect more data on the leukemia drug Clolar before the Food and Drug Administration will consider expanding the use of the therapy to previously untreated adults with acute myeloid leukemia.

Based on findings from a limited trial, Genzyme sought approval to market the drug to patients with the most common form of blood and bone marrow cancer in adults, the Cambridge, Mass., company said yesterday.

The FDA recommended a randomized, controlled clinical study before it would consider expanding Clolar’s use.

Clolar is approved for children with acute lymphoblastic leukemia (a cancer in which the bone marrow makes too many white blood cells) who have relapsed or are resistant to other treatments.

Genzyme plans to request a meeting with the FDA to discuss which studies will satisfy its requirements to use the drug for untreated adults.

From the Genzyme “About” page:

One of the world’s leading biotechnology companies, Genzyme is dedicated to making a major positive impact on the lives of people with serious diseases. Since 1981, the company has grown from a small start-up to a diversified enterprise with more than 11,000 employees in locations spanning the globe and 2008 revenues of $4.6 billion. In 2007, Genzyme was chosen to receive the National Medal of Technology, the highest honor awarded by the President of the United States for technological innovation.

With many established products and services helping patients in nearly 100 countries, Genzyme is a leader in the effort to develop and apply the most advanced technologies in the life sciences. The company’s products and services are focused on rare inherited disorders, kidney disease, orthopaedics, cancer, transplant and immune disease, and diagnostic testing. Genzyme’s commitment to innovation continues today with a substantial development program focused on these fields, as well as cardiovascular disease, neurodegenerative diseases, and other areas of unmet medical need.

Gainesville City Hall

Gainesville, FL – For his 18th birthday, Patrick Fitzpatrick asked for a pair of flashy track shoes for the upcoming season. For his 50th birthday, he was hoping to find a gift-wrapped ticket to the UF-Tennessee football game. For his 60th birthday, Fitzpatrick wanted to get arrested.

As a light drizzle fell on the large signs that read, “Would Jesus Feed the Homeless?,” “5th Meanest City” and “Homeless Rights are Human Rights,” near the stairs of Gainesville City Hall, Fitzpatrick and a few others broke the law Monday by handing out food to Gainesville’s homeless population. The law, passed in 2003, prohibits the noncity-sponsored distribution of food in front of City Hall.

“We’re breaking this law because we have a conscience,” said Fitzpatrick, who didn’t get his birthday wish. “I don’t care who they are — nobody can tell us who we can or can’t give a sandwich to.”

After the display of civil disobedience, Fitzpatrick, longtime homeless awareness activist, announced that he will run for the 4th District city commissioner seat, which will empty in March when its current holder, Craig Lowe, runs for mayor.

As the homeless munched peanut butter sandwiches and chocolate cake in cadence with faint, live accordion music, Fitzpatrick assured observers and reporters of the seriousness of his campaign and the need to resist the ever-growing power of current officials, who he referred to as “the robber barons.”

“The curve of politics typically goes in favor of the wealthy,” he said. “The curve of justice, however, goes to the poor.”

If elected, one of his first orders of business will be to rescind the 130-person limit on the amount of food served at the St. Francis House shelter. Fitzpatrick plans to establish a permanent place for homeless residents to stay. Danny Griggs, a Hawthorne resident who assists Fitzpatrick in caring for the homeless, believes the restrictions imposed at the St. Francis House need to be addressed immediately.

“I saw with my own eyes a pregnant woman get turned away because she happened to be No. 131,” he said. “That’s just not right.”

According to Griggs, one of the main problems contributing to Gainesville’s homeless problem is a misguided perception that all homeless residents have only themselves to blame for their circumstances.

“They’re smart people,” Griggs said, mentioning innovations made by homeless people to survive such as secretly cultivated gardens in which they grow assortments of vegetables. “Some of them just can’t do it by themselves.”

“Over there are the really stupid people,” he said, pointing to the tall buildings across from City Hall that house local businesses.

To David Wayne, who has been homeless for the past four months, the issue isn’t about politics or winning elections — it’s about getting the next meal. Wayne, whose battle with leukemia made his face jerk and contort as he speaks, sleeps near the courthouse. But despite his problems, Wayne said the efforts of homeless advocates like Fitzpatrick give him hope.

“You won’t see worry in my eyes; I got a secret,” he said, pointing to the sky. “My secret is God.”  (Source www.alligator.org)

Gainesville is the largest city and county seat of Alachua County. It serves as the cultural, educational and commercial center for the North Central Florida Region.

(recent  post by a person with Lupus featured on The Gazette)

In 2007, I was diagnosed with lupus and Lyme disease, and before getting sick, I would have never believed a positive attitude helped “cure” an illness. Then I got sick and brought my unhappy/negative attitude with me. No matter what medications I took, I was not getting well.

I’ve known many people with illness, some as serious as leukemia. Some are in remission, some have died. The ones who are well are the ones who had a positive attitude, the ones who died are the ones who held on to anger. I started to get better when I changed my attitude. I’m still not 100 per cent and I am still working on my happiness, but, in the meantime, I’m close to being fully functional again. And out of the ashes, I was lucky enough to find my passion in natural healing. I’m now working on my naturopathic degree in hopes of sharing my message and to help others who are ill. Anyone who took a human anatomy and physiology course would understand there is a definite connection between mind and body.

We would like to point out the one specific individual that was the first scientist to identify a chromosomal translocation as the cause of leukemia and other cancers which have led to dramatically improved survival rates.

Janet Davison Rowley, M.D., is the Blum Riese Distinguished Service Professor of Medicine, Molecular Genetics & Cell Biology and Human Genetics at The University of Chicago. She is an American human geneticist and the first scientist to identify a chromosomal translocation as the cause of leukemia and other cancers. Rowley is internationally renowned for her studies of chromosome abnormalities in human leukemia and lymphoma, which have led to dramatically improved survival rates for previously incurable cancers and the development of targeted therapies. In 1999 President Clinton awarded her the National Medal of Science–the nation’s highest scientific honor.