focuses on identification, characterization, and validation of genomic markers of prognostic and diagnostic significance in acute myeloid leukemia, or AML, with emphasis on the pediatric population.
An introduction to AML
Acute myeloid leukemia, or AML, is a rare, devastating and understudied malignancy with approximately 20,000 cases per year in the U.S., according to the SEER database. Only 65% of pediatric patients, younger than 21; 40% of adult patients, ages 21-65; and 10% of elderly patients, older than 65, survive five years after diagnosis.
Recurrent genomic alterations are known to confer prognosis and are used in guidelines to assign patients into risk classification and determine the intensity of treatment (i.e. recommendations for transplant). For the last five decades, the standard therapy for AML treatment has included an intensive combination of ara-C, daunorubicin, and etoposide , or ADE. However, ADE fails to induce remission in roughly 10-15% of children and 20% of adults.
Among those who achieve remission, roughly 40% of children and 70% of adults relapse. Over 90% of patients with resistant or relapsed AML die within three years. Thus, better biological understanding of AML is desperately needed to develop better treatment. Thankfully, over the past three years, eight new agents have been approved for the treatment of AML, including CD33-directed gemtuzumab ozogamicin (GO), FLT3 inhibitor midostaurin, the hedgehog pathway inhibitor glasdegib, the BCL2 inhibitor venetoclax, and Vyxeos (CPX351) a dual-drug liposomal encapsulation of ara-C and daunorubicin in a synergistic 5:1 ratio. Even after the recent approval of these drugs, ADE remains the backbone of AML therapy as these agents are primarily given in sequence or in combination with ADE.
Designing better AML treatment strategies
Dr. Lamba’s research program focuses on advancing the ability to design better treatment strategies to improve outcomes for AML by overcoming resistance, particularly in pediatric patients by leveraging a wide-range of multi-omics approaches. Significant heterogeneity in AML exists and is attributed to the presence of multiple recurrent cytogenetic features and genetic lesions. Although these features and lesions have been established over decades for defining risk groups and designing treatment strategies, there is still a huge gap in our understanding of the molecular landscape of AML. This lack of understanding hinders the development of novel treatment approaches that can provide individualization of drug therapy.
Dr. Lamba’s research spans from pharmacogenomic aspects to establishing and investigating molecular landscape and resistance mechanisms of profound prognostic relevance in pediatric AML. The ultimate objective of this research is to identify markers that could predict outcome in AML and integrate these with previously described prognostic factors to gain a comprehensive understanding of the mechanisms underlying drug resistance and inter-patient variation in AML treatment outcomes. Our results are directed toward designing personalized and more effective treatment regimens for AML patients and identification of novel therapeutic targets that could transform the current therapeutic regimens in AML.
To elucidate the molecular mechanisms of drug resistance and response in pediatric AML, we have evaluated the association of genomic variables with clinical outcome in the multi-center AML02 cohort and validated our results in independent cohorts of pediatric AML patients treated on Children’s Oncology Group, or COG, protocols. Highlights of our research include:
Identification of genetic-variants and gene-expression signatures that are predictive of ara-C response in AML using pathway-based and genome-wide approaches. We have recently developed a polygenic-risk score of significant prognostic relevance that is predictive of poor outcome in AML and holds the potential in individuating genomics-guided therapy augmentation.
Gemtuzumab ozogamicin, a re-emerging and promising new drug that binds to CD33. We have discovered CD33 polymorphisms of significant relevance and have developed potential novel antibodies recognizing different CD33 isoforms and are moving forward with development of novel therapeutic agents.
Our transcriptomic-based regression modeling approach has established a leukemic stem cell score (pLSC6) and a drug resistance score (ADE-RS5) that holds promising clinical utility in identifying poor-risk AML and accordingly may be used to design consolidation and maintenance therapies, or make transplant-related decisions.
We have recently established the genome, methylome, and transcriptome of AML prognosis in pediatric cohorts with hundreds of patients. These discoveries established differences in childhood AML as compared to adult AML and have led to promising novel therapies that are being evaluated in clinical trials. For example, we developed an innovative integrative analysis procedure to discover and confirm that reduced methylation and increased expression of DNMT3B associated with greater genome-wide methylation and worse outcome. Our DNMT3B discovery, first reported in December 2015 at the American Society of Hematology (ASH) meeting, motivated the evaluation of demethylating agents in the ongoing multicenter AML16 clinical trial [NCT03164057] that opened for enrollment only 18 months later. To date, AML16 has enrolled 126 patients at St. Jude, Dana-Farber, Stanford, and 10 other centers across the US.
We are currently pursuing the first systems biology characterization of pediatric AML that integrates five forms of high-dimensional molecular data with multiple clinical outcomes for hundreds of patients treated on three contemporary multi-center clinical trials. This machine learning systems biology-approach by integrated evaluation ofthe multi-level omics data will establish the most complete understanding of pediatric AML systems biology to date.
Finally, we are leveraging CRISPR/cas9 technology and have recently developed a custom CRISPR library-AMLRx2442 (representing AML prognostic genes, genes involved in AML-chemotherapy pharmacology and druggable-genome targeting genes with actionable and approved drugs) for evaluation of AML cell lines and primary leukemia cells. Integration of patient-data informed custom CRISPR/cas9 gene-knockout drug screening results would connect the loop back with patients to define and validate genes involved in relapse/resistance using multiple AML cohorts.
Overall, our results have multi-directional consequences: development of prognostic score that identifies patients at higher risk of disease resistance/relapse; establishing pathways of drug-resistance and identifying agents with potential to overcome resistance to standard chemotherapy. Using innovative machine learning tools that integrate multiple-omic profiles with multiple pharmacologic or clinical endpoints, we have successfully discovered and validated gene-expression and DNA-methylation signatures of prognostic relevance in multiple clinical cohorts. Coupling of genetic/epigenetic/metabolomic markers mediating antileukemic chemotherapy response and their integration into current prognostic features presents an opportunity to increase our accuracy in forecasting therapeutic outcomes in AML, allowing tailored, risk-stratified treatment approaches — a major advancement over the current strategy.
- Pathway-focused PGx approaches to design tailored therapy based on patient’s genotype
- PGx of gemtuzumab ozogamicin (GO)
- PGx of ara-C, daunorubicin and etoposide (ADE)
- Developing new CD33 antibodies targeting D2 isoform as potential therapeutics
- Transcriptomics-based scores as a diagnostic tool to refine high-risk AML and patient stratification for subsequent therapy
- Leukemic stem cell (pLSC6)
- Drug resistance scores
- Genome-wide/Targeted CRISPR/cas9 synthetic lethal screening in AML
- Metabolomic and Proteomic approaches to define pediatric AML and establish metagenomics and proteogenomics interactions of therapeutic relevance in AML
- GWAS in pediatric AML for defining prognostic biomarkers and risk loci
- Integrative multi-level omics systems biology approach to identify predictive markers of response/toxicity by simultaneous evaluation of multiple endpoints. (Collaboration Dr. Pounds)
- Pharmacogenomics of fludarabine, busulphan and thiotepa in pediatric leukemia patients receiving bone marrow transplant
- PGx to evaluate toxicities to multiple anti-leukemic agents in pediatric AML.
- PGx of Peg-asparaginase and methotrexate in pediatric AML