Improving Pediatric Outcomes in Oncology through Genomics

Within the past decade, target therapies have been prescribed using genomic data to more precisely diagnose cancer and predict future outcomes. The pediatric field is lacking by not targeting mutated oncogenic drivers and rare ALK translocated malignancies. Pediatric cancer does not have as many mutations, and many studies on focused on the disease state. New evidence shows that post therapy relapse samples accumulate more mutations and may lead to chemotherapy resistance.

A study with 102 children and young adults (up to age 22) involved exam sequencing of paired blood mononuclear cell and tumor DNAs along with tumor RNA sequencing. 69% had solid tumors. The study was designed to identify germ-line mutations that could cause an effect, tumor-specific alterations that would alter the histopathologic diagnosis, change risk status or both, and medically targetable somatic mutations.

Potentially actionable findings were found in 46% of cases and action was taken in 23 of those 42 patients (54%). A change of therapy was initiated for 14 patients (15%), a gremlin mutation was found to be clinically relevant in 9 patients, and 9 of the 14 patients had clinical benefit from the intervention.

This data is very relevant and suggests a promising field of research. With genomic sequencing, therapies were personalized in order to better target the cancer. As pharmacists, we should consider this and acknowledge that patients may require different treatment even with the same disease state. The research and sequencing in adults can and should be applied to children to better care for their cancer.

JAMA. 2015;314(9):881-883. 

Researchers have visualized the origins of cancer from the first affected cell

For the first time ever, scientists have watched cancer from the first affected cell and watched it spread in a live animal. The study used live zebrafish to track the development of melanoma over time. The fish all had a human cancer mutation as well as the loss of the tumor suppressor gene p53. In order to see this happen, the researchers made it so that individual cells could light up green if certain genes were expressed.

These cells express characteristics of stem cells which normally shut off after embryonic development, but are reactivated in certain cancer cells. The researchers discovered that the genes that were reactivated in the cancer cells were the same genes that are turned on during embryonic development. One of the researchers explained how this group of genes are also the ones that get turned on in human melanoma. This work could be used to potentially create drugs that target moles from becoming cancerous in humans.

The researchers proposed a new model of how cancer works. They proposed that the normal tissue has oncogenes activated and tumor suppressor genes are silenced or lost, but that cancer only occurs once the cell converts back to the embryonic state and starts dividing.

I think this study is really interesting because the researchers were able to see cancer from the first cells onward. This is groundbreaking research that will be useful for further studies so we can continue to learn to understand exactly what causes cancer.  My question for the class is: How useful do you think these findings are and how can we translate this into future human cancer studies?

 

Reference:

K. Kaufman, C. Mosimann, Z. P. Fan, S. Yang, A. J. Thomas, J. Ablain, J. L. Tan, R. D. Fogley, E. van Rooijen, E. J. Hagedorn, C. Ciarlo, R. M. White, D. A. Matos, A.-C. Puller, C. Santoriello, E. C. Liao, R. A. Young, L. I. Zon. A zebrafish melanoma model reveals emergence of neural crest identity during melanoma initiation.Science, 2016; 351 (6272): aad2197 DOI: 10.1126/science.aad2197

Newly Approved Protease Inhibitor Demonstrates Novel Route of Administration in the Treatment of Multiple Myeloma

Multiple myeloma is a common form of blood cancer that is diagnosed in about 86,000 people per year. The most commonly used treatments for multiple myeloma are protease inhibitors, or PIs. The first PI, bortezomib, was approved by the FDA in 2003 and can be administered intravenously to induce apoptosis in cancer cells by binding to and inhibiting the β5 site of the 20s proteasome. Bortezomib has several significant drawbacks, including the risk for peripheral neuropathy and the development of resistance and subsequent relapse for a majority of patients on this treatment. A second generation PI, carfilzomib, was introduced in 2012 and although it has a smaller risk of causing peripheral neuropathy it must still be administered intravenously.

Ixazomib, another second generation PI that was approved by the FDA in November 2015, represents a significant improvement over the previously available PIs. Ixazomib has a similar mechanism of action to bortezomib, but its higher specificity to the β5 site of the 20s proteasome means that ixazomib has a much lower incidence of peripheral neuropathy.  However, despite the similar mechanisms of action ixazomib may be used to treat bortezomib resistant patients. Perhaps the most important characteristic of ixazomib is its ability to be taken as an oral capsule as opposed to the intravenous administration that is required for other PIs. The most common side effects of orally administered ixazomib were manageable side effects, such as nausea and diarrhea. Treatment with ixazomib demonstrated a response in 34% of patients in the Phase II studies, and concurrent treatment of ixazomib and dexamethasone demonstrated a response in a further 34% of the population. Based on its mild side effects, efficacy, and convenience of administration, ixazomib represents a promising agent in the treatment of multiple myeloma. Perhaps this study demonstrates the need for further research into the development of more convenient, orally administered treatments to replace medications traditionally administered intravenously?

 

Muz B, Ghazarian RN, Ou M, et al. Spotlight on ixazomib: potential in the treatment of multiple myeloma. Drug Des Devel Ther. 2016;10:217-226

Novel Drug Therapy for Treatment of Relapsed Chronic Lymphocytic Leukemia

Chronic Lymphocytic Leukemia (CLL) is the most prevalent leukemia among adults. It is also one of the most commonly relapsing types of cancer. While chemotherapy and traditional forms of cancer treatment do prolong remission and overall survival rates, relapse occurs in practically all patients. The commonality of relapse in patients with CLL has prompted the discovery of novel drug targets in hopes of stopping the proliferation of leukemia cells in the body. Bruton’s tyrosine kinase (BTK) is a downstream signal proliferator in several pathways that are relevant to both tumor-cell survival and the ability for the tumor-cells to adhere to one another.

However, the inhibition of BTK results in the loss of immunoglobulins in blood serum which results in an increased risk of infection for those affected by BTK inhibitors. In addition, because the structure of BTK is vastly different from other tyrosine kinases it is a perfect therapeutic target. Ibrutinib is a first-in-class, small molecule drug that covalently binds to and inhibits the action of BTK, specifically its cysteine (C481) site. Ibrutinib is, however, not a very selective inhibitor as it also inhibits the action of many other protein kinases and causes severe side-effects. Second generation BTK inhibitor, acalabrutinib, is highly selective to BTK C481 and therefore has a lower side-effect profile than ibrutinib.

The response to acalabrutinib in early clinical testing was overwhelming with 98% of patients having reduction in lymphadenopathy (swollen lymph nodes) and 61% having concomitant lymphocytosis (elevation in blood-lymphocytes). Additionally, most adverses effects of the medication were not considered dangerous or life-threatening with most being mild headaches and diarrhea. Only two events of progression were reported in the study. All in all, acalabrutinib shows major steps in the reduction of relapses for CLL patients, and a new string of hope for those diagnosed with CLL.

Do you think this drug has the potential to become a first like treatment for leukemias? Could drugs like this lead to the end of chemotherapy?

 Article Link

Citation:

Byrd JC, Harrington B, et al. Acalabrutinib (ACP-196) in Relapsed Chronic Lymphocytic Leukemia. N Engl J Med. 2016;374:323-332