Targeted Therapies Prove Effective Against Head and Neck Cancers

Each year, more than 500,000 people are diagnosed with cancers of the head and neck. A recent study by researchers at Yale Cancer Center has identified a potential protocol that combines two targeted therapies to attack head and neck cancer. These cancers are known to be particularly difficult for patients, even those who are cured, as they can alter people’s appearances and their ability to eat and speak.

Cancer is generally the result of increased cell growth and proliferation, and one of the key proteins involved in that process is the Aurora kinase A (AURKA) protein. AURKA is responsible for regulating part of the cell cycle and interacting with p53-family proteins. Another important protein in a cell’s life cycle is the WEE1 protein. Both the AURKA and WEE1 proteins are involved in in these key cellular processes. During one phase of the cycle, the dividing cell creates “spindles” that help pull apart the two sets of DNA. AURKA is needed for the spindles to work properly, and WEE1 encourages the final separation of the cells.

Many cancer patients appear to show an increased level of the AURKA protein, but high AURKA levels may be associated with worse outcomes in patients with head and neck cancers. Researchers developed an ARUKA inhibitor called alisertib, but it was not effective on its own so researchers returned to the lab to look for other drugs to combine it with.

Research has shown that the WEE1 protein is able to boost the effects of cisplatin chemotherapy on head and neck tumors with p53 mutations and resulted in the creation of a WEE1 inhibitor called adavosertib. Researchers at Yale wondered if combining inhibitors for both the AURKA and WEE1 proteins could create a “synthetic lethal effect” against head and neck cancer.

Jong Woo Lee, PhD, the lead author of the paper, experimented with the combination of alisertib and adavosertib in human cells that had non-HPV-associated head and neck cancers and found that it killed more cells than either inhibitor on its own. Collaborators studied the effect further through in vivo models, in which tumors created from human cells were grafted into mouse models, and they found that the drug combination stopped tumor growth in these models.

Researchers are now designing an early clinical trial of the drug combination for patient testing. In a second trial, they plan to examine the effects of giving each drug alone, as well as in combination, to patients before surgery. The broad goal of the studies is to determine if combining AURKA and WEE1 inhibitors can act like a synthetic lethal therapy in other cancers that depend on AURKA and have p53 mutations.

Study Suggests New Standard for Kidney Cancer

Investigators at the Dana-Farber Cancer Institute recently completed a phase 3 clinical trial that could lead to changes in the standard treatment protocol for advanced kidney cancer. The trial tested a combination of the immunotherapy medication, avelumab, and axitinib, a vascular endothelial growth factor receptor (VEGFR) tyrosine kinase inhibitor (TKI), against sunitinib, another VEGFR TKI, which is currently the standard treatment for advanced clear-cell renal carcinoma, the most common form of kidney cancer.

This trial was the first to combine avelumab with an agent that targets one of the receptors controlling angiogenesis. VEGFR inhibitors, like axitinib and sunitinib, are designed to block the blood supply to tumors, starving them of essential nutrients. Immunotherapy medications, like avelumab, block an immune checkpoint called PD-L1, and activate the body’s T-cells so they are more effective in fighting cancer cells.

The randomized study consisted of 886 patients with previously untreated, advanced renal cell carcinoma. Results of the study showed that patients receiving the combination of avelumab and axitinib had a higher response rate than those receiving sunitinib, causing greater tumor shrinkage. The results for patients whose cancer cells were positive for the PD-L1 checkpoint showed a median progression-free survival (PFS) of 13.8 months in the combination group compared to 7.2 months in the sunitinib group. The PFS for the overall population was the same for the combination group, and was 8.4 months in the sunitinib group. Tumor shrinkage was 55.2% in the combination group compared to 25.5% in the sunitinib group who were positive for PD-L1.  

While PFS improved with the drug combination, researchers plan to continue follow ups with patients to determine if the combination of medications extends the overall survival rate compared to the standard regimen. Senior author of the study, Toni Choueiri, MD, hopes the results will lead to an FDA approval for the combination in the near future and a shift in the standard of care for patients with this difficult-to-treat cancer.

CA-170 May Help Fight Mesothelioma

Mesothelioma is a rare and extremely aggressive form of cancer that affects the lining around the lungs, heart and abdominal cavity. It is caused by exposure to asbestos, but symptoms often remain dormant for years or decades. It is difficult to treat and has a five-year survival rate of only 9%, according to the Mesothelioma and Asbestos Awareness Center. Recently, a new clinical trial has begun enrolling and treating mesothelioma patients with an experimental immunotherapy drug called CA-170 in hopes of improving the prognosis.

The current study is a Phase I, open-label dose-escalation and dose-expansion trial that is focusing on studying the safety and initial clinical efficacy of CA-170 in patients. Two dosages are being tested on study participants.

CA-170 is a dual inhibitor of the VISTA protein and the PDL1 protein receptor and is currently the only anti-VISTA therapy being studied. The VISTA protein is present in 90% of mesothelioma tumors and helps cancer cells avoid attack from the immune system. High levels of VISTA expression have also been noted in other cancers, including ovarian, endometrial and non-small cell lung cancer. This suggests that the results from this study could have broader impact if CA-170 proves effective against the VISTA protein.

The PDL1 receptor also stops the immune system from attacking a cancer cell. By stopping both the VISTA and PDL1 communications to the immune system that the cell shouldn’t be attacked, the immune system is able to recognize the cancerous cells and begins attacking the diseased cells.

There are several PDL1 inhibitors currently on the market, including Tecentriq and Imfinzi, which have shown promise in treating mesothelioma. Researchers hope that by combining these effects with a drug that is able to also inhibit the VISTA protein, they will be able to better treat mesothelioma tumors.

The mesothelioma cohort is actually a sub-section of a larger study that has been active since 2016. Other groups in the study are being observed for how CA-170 affects advanced solid tumors and lymphomas, but they focus on a different protein. So far, the drug has shown promising results, as it has been well tolerated with no significant toxicity, as well as preliminary signs of tumor shrinkage.

The Food and Drug Administration has not approved a new treatment for mesothelioma since 2004, when a combination of the chemotherapies, Alimta and cisplatin, became the standard treatment of choice.

What Are Tyrosine Kinase Inhibitors?

Cancer treatments have dozens of names and acronyms associated with them. Each type of cancer generally responds to a different medication, and even within a cancer type, there are subtypes depending on the mutations present in a specific tumor. Tyrosine kinase inhibitors (TKIs) are a form of targeted therapy that are used to treat many types of leukemia, as well as solid tumors such as non-small cell lung cancer (NSCLC). Targeted therapies have become extremely common in cancer treatment, because they are able to identify and attack cancer cells while causing much less damage to healthy cells.

TKIs block the action of enzymes called tyrosine kinases. Tyrosine kinases are involved in multiple cell functions, including cell signaling, growth and division. When these enzymes are overactive or mutated, they can cause cells to grow uncontrollable (resulting in cancer). TKIs work by blocking these enzymes, which, in turn, stops cancer cells from growing and helps slow  the disease down dramatically in many cases.

TKIs are used both as an initial treatment method, as well as in cases of resistance when treating cancer. Initial treatments are the first-line therapy used on a patient to treat a disease. If the initial therapy fails to work on the patient, meaning the cancer doesn’t respond or the person isn’t able to tolerate the side effects, another treatment option is often prescribed. Certain TKIs, such as imatinib mesylate and dasatinib, are used as first and second-line therapies, while other medications, such as bosutinib and ponatinib, are used generally when patients have failed one of the front-line treatments. Second- and other later line therapies are often created to specifically overcome resistances created by one or more earlier lines of treatment.

Patients with NSCLC and certain forms of leukemia are the most common recipients of TKIs. Patients with chronic myeloid leukemia (CML) are often treated with TKIs, because they are able to target the abnormal ALK or BCR-ABL protein, respectively that causes uncontrollable cell growth. TKIs block the protein’s function causing cells to stop growing and die.

TKIs are also used to treat Philadelphia chromosome-positive acute lymphoblastic eukemia (Ph+ ALL). Before the discovery of TKIs in the early 2000s, patients diagnosed with Ph+ ALL had less than a 20% chance of long-term survival. When TKIs were introduced into treatment protocols alongside standard chemotherapy, the 5-year survival rate more than doubled. Recent studies have shown that second-generation TKIs are even more effective than their predecessors at combating this disease.

Patients with NSCLC are also treated with TKIs, particularly those who have a overactive or mutated forms of epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK). Studies have shown that patients treated with EGFR TKIs have improved overall response rates and progression-free survival rates, as well as a better quality of life. Recently, second-generation TKIs targeting the T790M mutation of EGFR have become available for patients with this advanced form of NSCLC.  

Molecular Vulnerabilities Discovered in Cancer

Synovial sarcomas and rhabdoid tumors are two of the most difficult types of cancer to treat. Synovial sarcomas are found in the soft tissues and are most often diagnosed in young adults. Rhabdoid tumors typically develop in the brain, kidney and other organs of children under two. Both of these cancers are deadly and have survival rates around 30 percent, but a recent discovery of a molecular vulnerability by scientists at the Dana-Farber Cancer Institute could offer new treatment options.

Researchers discovered a “molecular machine” called ncBAF that regulates gene activity. This molecular machine, called a chromatin-remodeling complex, is essential to the development and maintenance of cancer. These complexes are made of proteins that determine how DNA is packaged in a cell and regulate which genes are expressed. Researchers found that disabling components of the molecule hindered the cancer’s ability to reproduce. Dr. Cigall Kadoch was senior author of the report published in Nature Cell Biology.

Kadoch’s team focused on a group of complexes called the SWI/SNF family. They found that the molecules travel to different locations in the DNA within a cell and impact the genes that are turned on, as well as the creation of proteins. It is estimated that 20 percent of human cancers are associated with mutations in the chromatin-remodeling complex, disrupting gene expression and causing tumors to develop.

Researchers found the ncBAF complex is essential for synovial sarcoma and rhabdoid tumors to maintain cell division and growth. Researchers believe that disrupting ncBAF could be the key to treating these tumors, deeming it a “synthetic lethal target.”

Kadoch and her colleagues further focused on the BRD9 subunit of the ncBAF complex, noting that there are current treatments under investigation focused on blocking BRD9. Researchers are also working on protein degraders that are designed to eliminate BRD9 in cells. Kadoch hopes her team’s findings will assist other researchers as they work on blocking the BRD9 protein and fighting cancer.

Combatting the EZH2 Enzyme

Chemotherapy has been the standard cancer treatment method for lung cancer, but it is known to cause problems, including harming healthy cells and not killing all cancer cells. These cells are often changed as a result of the chemotherapy, making them more difficult to treat with standard methods. As a result, these cells evade further treatment, causing the cancer to return. More recently, immunotherapy with checkpoint inhibitors have become the mainstay of first line and follow on therapy in various types of lung cancers.  

A recent study by Dr. Gaetano Gargiulo at the Helmholtz Association in Germany has discovered a potential way to treat cells that have been altered by chemotherapy treatment. His research was recently published in the Journal of Experimental Medicine and focused on non-small cell lung cancer (NSCLC), the most common type of lung cancer, which includes several subtypes.

While chemotherapy is often successful in stopping cells from dividing in NSCLC patients, aggressive cancer cells can survive the treatment and end up altered as a result. These remaining cells are dangerous because they have changed in a way that can leave doctors unsure as to what type of cancer they are dealing with and how to best treat it.

Dr. Gargiulo’s team investigated an enzyme, called Enhancer of Zeste 2 (EZH2), that promotes lung cancer. They treated test mice with drugs that inhibited EZH2, and soon found that it caused the cancer cells to become more aggressive due to inflammation in the cells. Instead of seeing this as a problem, researchers saw an opportunity to outsmart the cancer. The researchers encouraged the cells to become inflamed and then ambushed them by giving the mice an anti-inflammatory drug, leaving the aggressive cells exposed and vulnerable to treatment.

Early tests suggest this could be a potential strategy to explore in treating lung cancer patients. Gargiulo made a point of noting that making cancer more aggressive can be very dangerous, and researchers must be cautious when pursuing this experimental path.  

FDA Approves New Medications for Acute Myeloid Leukemia

Two medications, Daurismo and Venclexta, have passed the final rounds of review by the US Food and Drug Administration (FDA) and been approved for patients with acute myeloid leukemia (AML). These drugs are intended for use in patients who are not candidates for intensive chemotherapy. Intensive chemotherapy is not recommended for patients over the age of 75 or those with certain health conditions due to the severe side effects that it causes.

Daurismo, marketed by Pfizer, was tested in clinical trials in combination with a low-dose of the chemotherapy drug, cytarabine. Known as a hedgehog inhibitor, Daurismo is a targeted medicine that interferes with the hedgehog-signaling pathway. The hedgehog-signaling pathway is involved in cell differentiation and growth, and problems in this pathway can cause out-of-control cell growth and lead to certain types of cancers, such as AML. Daurismo was tested in a randomized clinical trial of approximately 100 people. Patients who received Daurismo in addition to cytarabine lived an average of four months longer than those who only received the chemotherapy.

The drug Venclexta is already available to patients with chronic lymphocytic leukemia, but the FDA expanded its approved indications to include AML after two non-randomized clinical trials. These trials measured the number of AML patients who went into complete remission, meaning there were no traces of cancer in the body, and how long they stayed in remission.

In the first trial, 37 percent of patients achieved complete remission after receiving Venclexta along with the chemotherapy drug azacitidine and stayed in remission for an average of 5.5 months. In the same study, 54 percent of patients who received Venclexta and decitabine, another chemotherapy drug, went into complete remission that lasted for an average of 4.7 months. In the other trial, 21 percent of patients achieved complete remission for an average of six months when Venclexta was used with cytarabine. Venclexta was developed by AbbVie and is marketed by AbbVie and Genentech USA Inc (Roche).

Both medications were reviewed under special FDA procedures that are used to speed up the approval process for medicines to treat serious illnesses without adequate alternatives. They were also granted orphan drug designation, which provides modest financial incentives to companies to encourage the development of drugs for rare diseases.

A Potential Vaccine for Glioblastoma Patients

A study by investigators at the Dana-Farber Cancer Institute suggests that neoantigens could play a role in treating glioblastomas. Patients in this study received a personalized vaccine that led to longer survival compared to most patients with glioblastomas, suggesting that selectively stimulating these tumors could be the key to curing them.

Glioblastomas are malignant brain tumors that are usually slow growing but can become aggressive. By the time these tumors are discovered, they are typically Grade IV, meaning they grow rapidly, have bizarre cellular appearances and easily infiltrate nearby brain tissue. They are also capable of forming new blood vessels (angiogenesis), which allows them to absorb more nutrients and continue growing. In addition to their location and rapid growth, glioblastomas are “cold” tumors, meaning they contain very few immune cells. Immune cells are recognized by the body as cells requiring action; since these tumors contain very few of those cells, the immune system does not respond properly.

To combat the lack of immune cells, David Reardon, clinical director of the Center for Neuro-Oncology at Dana-Farber, performed a study with a neoantigen vaccine for glioblastomas, published in Nature. The vaccine used in the study was a personalized ‘neoantigen’ serum that caused an immune response against glioblastomas. Like other cancers, glioblastomas contain DNA mutations that cause cells to reproduce rapidly and create tumors. Some of these mutations, including those in glioblastomas, cause cancer cells to display peptide molecules — or neoantigens — on the cell’s surface. Neoantigens are not present on healthy cells, making them relatively easy targets for the immune system.

To attack the tumor cells, researchers created personalized vaccines by removing and analyzing tissue from tumor and healthy cells in the patient. Once they identified which neoantigens were present in the tumor, proteins from the neoantigens were synthesized in a laboratory to form the base of the vaccine. After being administered, the vaccine encourages the body to create T-cells that migrate to the brain tumor, causing inflammation around the cancer cells. Then, the neoantigens in the serum “teach” the patient’s immune system how to detect and attack tumor cells.

The eight patients in the study received vaccines containing between seven and twenty neoantigen peptides. All of the patients ultimately died from their tumors, but they survived longer than average for glioblastoma patients. Reardon is encouraged by the results of this preliminary study.

“The next step is to add an immunotherapy drug called a checkpoint inhibitor, aimed at freeing the immune response from molecular ‘brakes’ so that the T-cells can react more strongly against the tumor,” Reardon said.

The combination of a neoantigen vaccine with a checkpoint inhibitor should lead to a stronger immune response and potentially extended survival without tumor spread and thus, the possibility of a cure.

Nobel Prize in Medicine Honors Immunotherapy Researchers

For many years cancer treatment involved chemotherapy, surgery and radiation to stop the growth of cancer cells. But in the past few decades, researchers began studying how the human body’s immune system could be bolstered to fight the disease itself.

After losing friends and family to cancer, James Allison and Tasuku Honjo each became interested in studying cancer and understanding the way it changes the body, particularly immune cells. Their groundbreaking research opened the door for immunotherapy.

Allison’s research focused on the CTLA-4 protein, which regulates T-cells, the workhorses of the immune system. Oftentimes the protein blocks the immune system from attacking cancerous cells. However, Allison developed an antibody to inhibit the CTLA-4 protein and in 2011, the FDA approved ipilmumab, or Yervoy, to treat advanced melanoma.

Yervoy led to the creation of a new drug class called checkpoint inhibitors. Checkpoint inhibitors stop proteins from blocking an immune response and free T-cells to attack malignant tumors. Studies have shown that these inhibitors work in patients with melanoma, as well many other solid tumors.

In 1992, Tasuku Honjo, a professor of immunology at Kyoto University, discovered a protein called Programmed Cell Death Protein 1 (PD1), which is on the surface of immune cells and determines if cells grow normally or turn cancerous. His research showed that the protein inhibits the function of the body’s natural immune defenses.

Working from this discovery, a 2012 study showed that blocking the protein could help the body fight cancer. This led to the development of pembrolizumab, or Keytruda, and nivolumab, or Opdivo, both approved in 2014 to treat melanoma. Subsequent clinical trials have demonstrated the safety and efficacy of these and other checkpoint inhibitors in many different forms of solid tumors, including lung cancer, head and neck cancer, and others.

The groundbreaking research by both Allison and Honjo has opened new doors for cancer research and led to the creation many checkpoint inhibitors, leading to the extensive study of these new medicines. Their discoveries have given many cancer patients a chance at living more normal lives and living longer.  

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.