A new feature in Leukemia & Lymphoma: “Emerging drug profile”

Decoding of the six billion bases of the human genome not only provided fundamental knowledge of the complete genetic sequence of a normal cell, but also opened access to the capacity to compare anomalies in the cancer genome with its healthy counterpart, providing insights into the molecular underpinnings of the disease. While it is challenging to determine whether the revealed aberrations are in fact causal or driver(s) of the disease, they provide a potential therapeutic target and have had a transformative impact that became the basis of personalized and tumor-specific medicine. For hematological malignancies, these advances are moving at an exponential rate. First, the acute myeloid leukemia (AML) genome was sequenced a few years ago, followed by several studies in myelodysplastic syndromes (MDS) and AML. A landmark paper with genomic and exomic sequence from patients with multiple myeloma was also published recently, and during the last 2 years, several reports on genome sequences of patients with chronic lymphocytic leukemia (CLL) have defined additional new genetic lesions. Gene array profiling has also defined several subsets of myeloma as well as new subsets of lymphomas.

Surgery, radiation and chemotherapy are the three tenets of cancer treatment, and very impressive progress has been made in the chemotherapeutic world to treat cancer in general and hematological malignancies in particular. Due to the disseminated nature of the diseases, leukemia and myeloma treatment relies exclusively on novel therapeutics. Pediatric leukemias, an epitome of success with high cure rates, also rely totally on combinations of chemotherapeutic drugs, while impressive progress has been made in therapeutic development in lymphomas. Importantly, it is easier to test novel therapeutic approaches with validation of biomarkers in hematological malignancies where access to pure target tumor tissue is feasible. Collectively, these observations underscore current and future discoveries in medicine and help to tailor medication for these patients.

Rationale for this new feature in the journal

The knowledge of cellular processes at a molecular level continues to provide unprecedented opportunities for rational approaches to the design of therapeutics that are targeted at the cause of disease. Fueled by an increasingly detailed understanding of the human genome and the development of remarkable technological advances, it is clear that the era of personalized medicine has truly arrived. While sequencing of an individual patient's tumor genetic make-up is at its infancy, is expensive, has error rates and is time consuming (especially complex analyses of daunting data to obtain meaningful and applicable endpoints), attempts to utilize available knowledge of identified lesions in therapeutics is exponentially ongoing. During the last decade an unprecedented number of new drugs have been tested for hematological malignancies, and several innovative agents and strategies have become standard of care for leukemias, lymphomas and myeloma.

Genetic make-up of a disease and targeting mutations, overexpressions and translocations are here to stay. A plethora of biopharmaceutical research industries, drug companies and individual scientists are designing, optimizing and developing novel therapeutics that attack genetic abnormalities rather than the whole tumor or the healthy tissue. A decline in untoward toxicity further emphasizes the importance and utility of such targeted therapeutics. Biochemical and genetic bioassays, isogenic cell line systems, patient-derived mouse tumor models and availability of target tissue from patients further propel this research.

Implications and consequences of such attempts have resulted in astonishing success stories in leukemias, lymphomas and myeloma. During the past two decades there has been an explosion of novel treatment options for patients with liquid tumors. Targeting the pathophysiological lesion in early stage chronic myeloid leukemia (CML) has become a poster child of personalized medicine. These tantalizing scientific discoveries, the near and far future of treatment of hematological malignancies, and phenomenal growth in research of novel drug development have all provided an impetus for us to initiate a new feature: “Emerging drug profile,” in Leukemia & Lymphoma.

What will be covered in this new feature and what are the objectives?

This new feature of the journal will focus on using an understanding of the biology of malignant disease as a rational basis for developing novel interventions and testing them in preclinical and importantly in clinical settings. These agents will include novel cytotoxic agents and tumor biology-based targeted drugs, as well as multi-targeted modalities. Chemically and biologically, they could be small molecule inhibitors, antisense and siRNAs, gene therapy agents, antibodies and immunotherapeutics, peptidomimetics, and more. While Food and Drug Administration (FDA) approval is not a requirement for selection, use in the clinic and patient-based knowledge are required.

Each article in this novel feature will focus on a single compound or a drug group and will include the rationale for the synthesis and design, chemical structure with available and alternative names, metabolism of the drug in target cells, mechanism of action including cellular and molecular targets of the compound, basis of drug resistance (if known) and preclinical investigations using model systems. Major emphasis will be placed on the knowledge obtained during clinical phase I, II and/or III trial outcomes with pharmacokinetic and pharmacodynamic endpoints, biomarker validations, and toxicity and efficacy of the drug. Finally, cost–efficacy analyses and the future of the novel agent will also be discussed.

The major goal of this feature is to provide comprehensive yet critical knowledge of new agents to basic academicians whose research focuses on hematological malignancies, as well as clinical hemato-oncologists. A summarized table will list pertinent information about the drug for an “at a glance” review.

All articles will be by invitation; however, we are willing to consider submitted proposals from scientists or clinical researchers. To ensure that all aspects are emphasized and included, these manuscripts will be peer-reviewed prior to publication. While issue versions may take time, “Just accepted” and “Early online” releases will guarantee and preserve timely dissemination of knowledge.

Inaugural article

The current issue of the journal presents an inaugural article from John Byrd's group on cyclin-dependent kinase inhibitors in general and flavopiridol in particular. While the article focuses on application in CLL, the potential scope of these agents is well beyond CLL. The next article has been charted to be published within 3 months and will be on ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor. This feature is planned to appear in the journal from now on every 3 months.

Acknowledgement

The author acknowledges grant support from the NCI and Leukemia and Lymphoma Society.