The Mystery of TP53 Unraveled

Mutations within a person’s DNA is one of the most common causes of cancer. p53 is one of the most commonly mutated genes among cancer patients and is a tumor-suppressor that works to regulate cell division and prevent cells from reproducing too quickly. However, when the DNA is mutated, the gene can lose this function and allow cells to grow out of control. Mutations in p53 are found in almost every kind of cancer, including lung, ovarian and laryngeal, among others.

For years, this mutation has intrigued scientists, as the DNA changes can occur at over 1,100 sites within the gene, though there are places, called “hot spots,” where mutations most frequently occur.

A recent study published in Nature Genetics by researchers from the Dana-Farber Cancer Institute, the Broad Institute of MIT and Harvard, and others, found that hotspot mutations are not more likely to produce cancer than mutations at other points within the genetic code.

The study used the newest technology available to create a library of all possible variants of the p53 gene — 8,258 in total. After sequencing the genes, researchers compared hot spot mutations to others and found that they were no more likely to promote cancer than mutations in other locations. They concluded that the tendency of mutations to occur in those locations is due to the way mutations occur and which parts of the body are exposed to carcinogens.

“This indicates we’re correct that mutations in p53 are focused on certain hot spots because those spots are targeted by the specific carcinogens to which cells are exposed,” said William Hahn of Dana-Farber in an interview. Hahn was the senior author of the study and serves as the deputy scientific officer at Dana-Farber.

Understanding the role gene mutation plays in causing cancer is imperative as gene sequencing becomes more common in cancer treatment.

Yale Study Affirms Treatment Guidelines for Polycythemia Vera

Polycythemia Vera (PV) is a deadly form of blood cancer that occurs when a mutated gene causes bone marrow to create extra red blood cells. The additional cells cause the blood to thicken, slowing its movement through veins and increasing the risk of blood clots. Patients over the age of 60 are at the highest risk for death related to PV. Standard treatments for this condition are phlebotomies and cytoreductive therapy with the drug hydroxyurea. Hydroxyurea (HU) is the more commonly used therapy, but both solutions are often underutilized in PV patients, according to the Yale School of Medicine.

Investigators at Yale recently performed a study of high-risk PV patients and their treatment methods to determine the best course of action for improving life expectancy. The high-risk PV patients involved were 66 years or older, with the median age being 77. Investigators searched patients records for evidence of thrombotic events, as well as treatments used in the past.

Of the 820 patients in the study, those who received phlebotomies had a 35% reduction in death and a 48% reduction in the risk of developing blood clots. When patients also received HU, researchers found that patients who used the medication longer had a lower risk of death.

Phlebotomies are used as a therapeutic “bloodletting” process for PV patients to reduce the amount of blood in their body while HU is used to suppress the bone marrow’s ability to produce excess red blood cells. The study found that a combination of the phlebotomies and HU saved lives, but it also showed that most patients were not receiving these recommended treatments. Analysis showed that almost 40 percent of PV patients were under-treated, receiving neither the recommended treatment nor just phlebotomies. Researchers in the study hope that their results will raise awareness of the two treatment options available for PV patients and the improved outcomes when both are used.

Immunotherapy Offers Melanoma Patients New Hope

Metastatic melanoma is one of the most difficult forms of cancer to treat, with survival rates as low as 15% for those with a stage IV diagnosis. These low survival rates began to improve with the 2011 approval of ipilimumab, the first checkpoint inhibitor. Checkpoint inhibitors work on T-cells and reactivate the immune system so it continues fighting cancer cells. Nivolumab is another checkpoint inhibitor that is also used to treat melanoma patients, alone or in combination with other medicines. A recent study at Dana Farber tested combining ipilimumab and nivolumab in patients with advanced melanoma who had not previously been treated. Results of the study showed that 53 percent of patients who received this combination of drugs were alive four years later, a remarkable result in melanoma clinical research.

The study followed 945 patients who had untreated and inoperable stage III or stage IV melanoma. They were separated into three groups, with one receiving the combination of nivolumab and ipilimumab, another receiving just nivolumab and the final group receiving just ipilimumab. Fifty-eight percent of patients treated with the two drugs had their cancer shrink, compared to only 45 percent of patients who received nivolumab alone and 19 percent for those who received ipilimumab alone. Additionally, several patients treated with the combination had their tumors disappear completely.

The median length of survival for patients varied greatly, ranging from 19.9 months in the ipilimumab group to a currently unknown number in the group treated with both drugs, because patients continue to do well and a median outcome cannot yet be established.

Treatment was given to patients in this study until they received the maximum clinical benefit, were experiencing unacceptable side effects or the patient asked to have treatment discontinued. For patients who survived four years, 71 percent of those treated with the drug combination were no longer receiving treatment along with 50 percent of the nivolumab group and 39 percent of the ipilimumab group being off treatment as well.

Patients who received the combination of drugs experienced a higher rate of adverse side effects — 59 percent — compared to 22 and 28 percent in the nivolumab and ipilimumab groups respectively. Despite these side effects, authors of the study believe this is an important discovery for melanoma patients and will improve long-term survival rates in the coming years.

Targeted Cancer Therapy

Since cancer involves the rapid reproduction of cells, most forms of treatment, like chemotherapy, target and kill rapidly dividing cells, regardless of whether or not they’re cancerous. Targeted therapy, also known as a form of precision medicine, is a new type of treatment that is becoming a focus in cancer research because it works on stopping and killing cancer cells without harming other cells, a common issue with chemotherapy.

Precision medicine involves treating a patient’s tumor based on the genetic change in the cancer cells (either in malignant blood cells or in the solid tumors themselves) and interfering with proteins that help cancers grow and spread. These medications work in a variety of ways to target the cancer, including helping the immune system destroy cancer cells, stopping the cancer cells from growing, killing the cancer cells and starving the cancer of stimulants (such as hormones)  it needs to reproduce and grow.

This therapy requires doctors to have a genetic understanding of the cancer and allows for more personalized treatment.  In some cancers like non-small cell lung cancer, forms of chronic leukemia, and types of breast cancer, these molecularly targeted therapies have become a standard of care.  It also is being studied in many clinical trials with extremely positive results. In order to receive these treatments, a patient must undergo a test to see if the genetic change being targeted is present in their tumor. This test is often a blood sample or a biopsy where the doctor removes a sample of the cancer and then the DNA is sequenced to look for genetic changes. If the changes match the targets of the therapy, the patient may be a good candidate to receive the drug. The results have been extremely promising and indicate that this may be an area where many new discoveries are made in the coming years. Several targeted medicines (such as ponatinib and brigatinib) have been approved and are widely used by patients whose cancers have been genetically defined.

What is CAR-T Cell Therapy?

Doctors have been fighting cancer for decades, but until now most treatment has been based largely on chemotherapy and surgery. One of the new avenues cancer researchers are exploring is CAR-T cell therapy, with the hope that it will provide more personalized treatment for cancer patients.

CAR-T cell therapy, sometimes described as a “living drug,” works by extracting the patient’s T cells, which are the cells that recognize and kill infected cells, and modifying them so they’re better able to fight cancer. 

In order to create CAR-T cell therapy, some of the patient’s blood is taken and the T cells are separated and then genetically modified. Through the modification process, the cells produce receptors on their surface called chimeric antigen receptors, or CARs, which allow the cells to recognize and attach to a specific protein on the tumor cells. When the cells are reintroduced to the patient’s body, they multiply, recognize the cancer cells and then kill them.

As of 2017, two CAR-T cell therapies have been approved by the FDA as a standard treatment option, including one for the treatment of children with acute lymphoblastic leukemia (ALL) and the other for adults with advanced B-cell lymphoma (DLBCL). CAR-T cell therapy has expanded the range of options for patients who previously didn’t have many therapeutic choices. For example, those with ALL who suffered a relapse after intense chemotherapy or a stem cell transplant usually did not have another way to fight the disease, but CAR-T cell therapy can now offer them another highly effective option.  The greatest challenge is managing the potential toxicities of these CAR-T therapies when given to patients with these blood cancers. Physicians are working diligently to try to apply CAR-T treatment to patients with solid tumors.  So far, efficacy has been limited. 

Nicole Elizabeth Berger’s Exciting Year

It’s half way into year and already 2018 has been a whirlwind for Nicole Elizabeth Berger. Nicole starred in the recently released film, All At Once. All At Once is a family drama that focuses on an upcoming artist whose life is turned around when he gained guardianship of two young girls after their parents, who were his best friends, were killed in 9/11. The film was originally shown at the Napa Valley Film Festival in 2016 and was released for streaming and DVD in April 2018.

Nicole recently wrapped up filming Clover in Buffalo, NY. Clover is a dramatic crime film about two brother who have to go on the run and protect a teenage girl who is witness to a murder. Nicole plays the film’s namesake, Clover. The film is set to release in early 2019.

Nicole also just finished filming a fantasy-reality film, The Place of No Words. The film centers around 3-year-old, Bodhi, as he battles the complexities of an adult world with his father. The film takes place in Snowdonia, Wales and Nicole plays Esmeralda, a fairy who interacts with the characters in the film.

When Nicole isn’t on set, she is attending Palm Beach Day Academy in Palm Beach, Florida, and partakes in the school’s theater program. This May, she played Maria in the school’s production of West Side Story. Last year, she starred as Ms. Honey in the school’s production of Matilda. In May, she also was awarded top drama award for a graduating senior at Palm Beach Day Academy, the Amory L. Haskell Award.

 

Boys & Girls Clubs of Palm Beach County Start Construction on New Teen Center

Harvey Berger gives back to many organizations he is dedicated to, especially to those in his local community. The Boys and Girls Club of Palm Beach County works with young people to reach their potential and make sure they are on track to graduate from high school. After reaching a $6 million fundraising goal, the organization has broken ground for phase 1 of the Smith & Moore Family Teen Center that will open in Belle Glade.

Plans for the new Teen Center were put into motion after the current location found themselves forced to turn away young people every day because it lacked the facilities and staff, only being able to serve 321 members. The Smith & Moore Family Teen Center will be able to offer academic, social and cultural activities for 900 members and will offer career prep programs.

“We are going to set the standard as the number one advocate for Belle Glade youth during out-of-school time.”- Jaene Miranda, president and CEO of BGCPBC

In mid-April, the Boys & Girls Club of Palm Beach held a ceremonial groundbreaking. The new state-of-the-art location will be two-stories, 13,000 square feet, and provide necessary after-school resources for the Belle Glade youth. BGCPBC is now ready to move to phase 2 of the $10 million campaign and is now looking to raise an additional $4 million to go towards an endowment fund that will keep the facility up and running.

Radioimmunotherapy | An Overview

Radioimmunotherapy is a combination of both radiation therapy and immunotherapy. Immunotherapy refers to treatments that use the body’s own immune system to combat cancer.

Several specific types of immunotherapy engage monoclonal antibodies. These antibodies then target select antigens that exist on the surface of cancer cells. They will then attach to cancer cells and act as a “disease-fighters” in the immune system.
Monoclonal antibodies, without radionuclides attached, are commonly used to treat cancer. These monoclonal antibodies are called “naked antibodies.” When conjugated or attached, monoclonal antibodies are paired with a radioactive substance and injected into the bloodstream. When used in radioimmunotherapy, they often travel and bind to cancer cells and deliver high doses of radiation directly to tumor cells. These conjugated monoclonal antibodies will then target the antigen directly. This specific approach is notably less damaging to the existing normal cells in other parts of the body as opposed to naked antibodies.

Radiolabeled antibodies such as ibritumomab tiuxetan attach to the CD20 antigen found on lymphocytes when treating non-Hodgkin lymphoma. Lymphoma starts in the a type of white blood cells known as lymphocytes and will then travel throughout the body and settle into several places, simultaneously.

Notably, researchers have begun studying antibody pairings with different radioactive agents and their potential uses in treating many other blood cancers or solid tumors. These cancers include prostate cancer, melanoma, ovarian cancer, leukemia, high-grade brain glioma, and colorectal cancer.

How Clinical Trials Advance Cancer

Dana-Farber Cancer Institute’s Director of the Early Drug Development Center, Geoffrey Shapiro, MD, PhD, addressed many questions that individuals often have regarding clinical trials. Additionally, he discussed how cancer treatment overall can be improved. The DFCI’s Early Drug Development Center specializes in conducting phase I clinical trials.

Shapiro discussed the importance of clinical trials noting that they are they are necessary in determining the safety and efficacy of new cancer drugs or drug combinations. He specifically noted the degree of care and attention to control necessary to generate a substantial enough amount of data that will ultimately allow medical scientists the ability to determine whether a drug is safe, what the appropriate dosage should be, and how effective the drug is.

When considering the advances made in clinical trials, Shapiro highlighted cell-cycle related agents, including CDK inhibitors. CDK inhibitors can prevent the proliferation of cancer cells and have transformed the treatment of estrogen receptor-positive breast cancer. Shapiro and his team are now extending the uses of these drugs to other diseases, including lung cancer, glioblastoma, and some forms of lymphoma and sarcoma.

While DFCI does extremely well in filling its clinical trials, nationally, the percentage of cancer patients participating in trials is alarmingly low. One of the most meaningful ways cancer patients can impact and continue to progress cancer treatment is by enrolling in a clinical trial. To learn more about Dana-Farber’s clinical trials, read Shapiro’s full interview.

The First U.S. Commercial Implants of Innovative EluNIR™ Drug-Eluting Stent Announced

In early January, Medinol and Cordis announced that the EluNIR™ drug-eluting stent (DES) was used commercially for the first time in cases in the United States. The procedures using the EluNIR™ were performed at two prestigious hospitals, New York-Presbyterian Hospital/Columbia University Medical Center and the Piedmont Heart Institute.

Medinol’s Executive Chairman, Harvey Berger, M.D., stated that the commercial launch of the EluNIR drug-eluting stent is a major step forward for Medinol and for patients with obstructive coronary artery disease.  This new stent system has important advantages for interventional cardiologists who are always looking for better and more effective ways to safely open occluded or narrowed vessels. Harvey Berger, M.D. to work with Medinol’s core business of interventional cardiovascular devices, in addition to its businesses developing sub-millimeter implantable sensors, unique percutaneous aortic valves and other complementary products.

The New York-Presbyterian Hospital/Columbia University Medical Center’s Director for Interventional Vascular Therapy, Martin B. Leon, M.D., noted, “Our first patient cases with the EluNIR™ stent went perfectly and we are enthusiastic about the overall performance including the uniform vessel coverage and the delivery system with the metallic spring tip, which is unlike any other product in the market. I have been following Medinol for over 20 years and am excited to see yet another one of the company’s innovative products launch in the U.S. market.”

The EluNIR™ stent was approved for the treatment of patients with narrowing or blockages to their coronary arteries. It is currently being distributed to cath labs throughout the United States by Cordis. The stent system is designed to help clinicians easily deliver this new DES in highly complex anatomy and disease.

“The physicians and staff at Columbia and Piedmont have played pivotal roles in the evolution of the EluNIR™ stent,” said Dr. Yoram Richter, chief scientific officer at Medinol. “We are honored to have the first commercial cases with EluNIR™ performed at such notable institutions. This event marks another step in Medinol’s legacy, which has continued to stretch the limits of innovation, starting with our NIR stent in 1996.”

Under a long-term distribution agreement between Cardinal Health and Medinol, Cordis was given Cardinal Health’s interventional vascular business, which includes the rights to sell Medinol’s coronary stent portfolio. This portfolio now includes the EluNIR™.