Abhijit Patel, MD, PhD
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Research Summary
In the Patel Lab (www.patel-lab.org), we are seeking to develop innovative strategies to diagnose, characterize, and monitor cancer with the ultimate goal of improving patient outcomes. Our research aims to understand and exploit cancer-specific signals within DNA fragments that are shed from tumor cells into a patient’s bloodstream. We are developing ultrasensitive diagnostic tools to enable measurement of trace amounts of these circulating tumor DNA molecules via analysis of genomic and epigenomic signatures. In parallel, we are conducting validation studies to establish the utility of these technologies for various clinical applications including early detection of new and recurrent cancers.
Our research draws upon expertise from diverse fields such as clinical oncology, molecular biology, chemistry, computer science, and microfluidics. We rely on extensive collaborations with both scientists and clinicians, and we are always open to new collaborations from investigators with good ideas.
Extensive Research Description
The release of nucleic acids from tumors into the bloodstream has been well documented in patients with various types of cancer. Recent technological advances are making it possible to analyze these circulating DNA and RNA fragments in ways that are proving to be clinically informative. To better understand the biological features and limitations of circulating nucleic acids, further improvements in assay methods are still needed. Our research efforts are focused on developing more robust analytical methods and on establishing the clinical utility of these methods.
ASSAY DEVELOPMENT:
Circulating tumor DNA
Tumor-derived DNA fragments in the circulation can be distinguished based on the presence of cancer-specific mutations. However, these mutant DNA copies are often obscured by a relative excess of wild-type background DNA in the plasma. In patients with early stage tumors or minimal residual disease following treatment, the fraction of mutant tumor-derived DNA in plasma can be well below 1 in 1,000. Detection of such low-abundance DNA variants poses a significant technical challenge, especially if one has no prior knowledge of the tumor’s mutation profile. We have developed methods to enrich mutation-prone regions of plasma DNA by highly multiplexed PCR. We use next-generation DNA sequencing technologies to oversample thousands of copies of these mutation-prone genomic regions, allowing rare sequence variants to be identified and enumerated. However, the sensitivity of this approach is limited by sequencer errors and PCR misincorporations, both of which might be mistaken for true mutant copies. To overcome this limitation, we have devised molecular and computational error-suppression strategies that enable ultrasensitive detection of rare mutant copies with broad mutation coverage.
High-throughput RNA profiling
Tumors are known to shed RNA molecules into blood. These circulating RNAs are surprisingly stable when bound to serum proteins or when encapsulated within tiny vesicles called exosomes. Such tumor-derived RNAs are showing great promise as biomarkers for cancer diagnosis and treatment monitoring. To facilitate analysis of RNAs from many patient samples in a high-throughput, low-cost manner, we have developed a method called META RNA profiling (for “modular early-tagged amplification”). The method is able to quantify a broad panel of microRNAs or messenger RNAs simultaneously across a large number of samples. It uses a next-generation sequencing readout, but demands far less sequence depth than existing digital RNA profiling approaches. An up-front quantitative tagging scheme allows all samples to be pooled, simplifying downstream processing steps and reducing inter-sample variability. While this approach can be applied to RNA samples derived from a variety of biological sources, we are using it as a tool to analyze gene expression in tumors and in clinical biofluids.
CLINICAL APPLICATIONS:
Liquid biopsy
The ability to sample tumor-derived nucleic acids in blood provides an opportunity to analyze a tumor’s mutations and gene expression signatures without requiring an invasive procedure to obtain a tissue specimen. Such information can be used to personalize cancer therapy, as drug choices are often guided by knowledge of a tumor’s genomic profile. Moreover, because tumors are known to be heterogeneous, a tissue biopsy taken from a single tumor site might miss critical genetic features present in other metastatic sites within the same patient. Because blood contains a sampling of nucleic acids derived from all tumors in the body, it is likely to enable a more comprehensive assessment of genomic heterogeneity. We are testing these concepts using clinical samples from patients with various types of cancer.
Assessment of treatment response
As is true for many protein biomarkers, quantitative changes in the levels of circulating nucleic acids appear to be correlated with treatment response. This may prove useful in assessing the response of tumors for which good serum protein markers are not available. We are also investigating whether unique aspects of nucleic acid specificity and kinetics can be exploited to complement information obtained from protein markers.
Emergence of treatment resistance
Genomic profiles of tumors are known to evolve over time. This can be especially important when a therapy leads to the selective proliferation of tumor cell populations containing mutations that confer treatment resistance. Therapy can be modified if the emergence of resistant clones is documented by repeating a biopsy, but such invasive procedures can be risky and impractical. We are evaluating whether nucleic acids in blood can be used to noninvasively track genomic and transcriptomic changes in tumors over time. Might we be able to predict treatment resistance before it becomes clinically evident?
Early detection of new and recurrent cancer
It has long been one of the grand challenges of oncology to detect tumors at their earliest stages, when treatment is more likely to be curative. However, efforts to develop blood tests for early cancer detection have had limited success because of the difficulty in identifying serum protein biomarkers that are sufficiently cancer-specific. Circulating tumor DNA may be a better-suited marker for cancer screening because tumor-specific somatic mutations can be used to distinguish tumor-derived DNA molecules. Since cancer-associated mutations should rarely be found in the plasma of healthy individuals, false-positive results are expected to be extremely uncommon. Furthermore, because there is no physiologic background, a small amount of mutant DNA released from an early-stage tumor should be detectable if the technical background of the assay can be minimized. Similar principles apply to the detection of small amounts of residual or recurrent disease following curative-intent therapy. We are keenly interested in evaluating whether our ultrasensitive ctDNA assay can be used for early detection of new or recurrent tumors.
Coauthors
Research Interests
Chemistry; DNA; Medical Oncology; Molecular Biology; Biomarkers; Microfluidics
Selected Publications
- Selective multiplexed enrichment for the detection and quantitation of low-fraction DNA variants via low-depth sequencing.Song P, Chen SX, Yan YH, Pinto A, Cheng LY, Dai P, Patel AA, Zhang DY. Selective multiplexed enrichment for the detection and quantitation of low-fraction DNA variants via low-depth sequencing. Nature Biomedical Engineering 2021, 5: 690-701. PMID: 33941896, DOI: 10.1038/s41551-021-00713-0.
- Tumor DNA Mutations From Intraparenchymal Brain Metastases Are Detectable in CSF.Cheok SK, Narayan A, Arnal-Estape A, Gettinger S, Goldberg SB, Kluger HM, Nguyen D, Patel A, Chiang V. Tumor DNA Mutations From Intraparenchymal Brain Metastases Are Detectable in CSF. JCO Precision Oncology 2021, 5 PMID: 34250381, PMCID: PMC8232069, DOI: 10.1200/PO.20.00292.
- META RNA profiling: Multiplexed quantitation of targeted RNAs across large numbers of samples.Narayan A, Johnkennedy R, Zakaria M, Lee V, Patel AA. META RNA profiling: Multiplexed quantitation of targeted RNAs across large numbers of samples. Methods (San Diego, Calif.) 2019, 152: 41-47. PMID: 30308315, PMCID: PMC6311137, DOI: 10.1016/j.ymeth.2018.09.012.
- Overall survival is improved when DCIS accompanies invasive breast cancer.Kole AJ, Park HS, Johnson SB, Kelly JR, Moran MS, Patel AA. Overall survival is improved when DCIS accompanies invasive breast cancer. Scientific Reports 2019, 9: 9934. PMID: 31289308, PMCID: PMC6616329, DOI: 10.1038/s41598-019-46309-2.
- Early Assessment of Lung Cancer Immunotherapy Response via Circulating Tumor DNA.Goldberg SB, Narayan A, Kole AJ, Decker RH, Teysir J, Carriero NJ, Lee A, Nemati R, Nath SK, Mane SM, Deng Y, Sukumar N, Zelterman D, Boffa DJ, Politi K, Gettinger S, Wilson LD, Herbst RS, Patel AA. Early Assessment of Lung Cancer Immunotherapy Response via Circulating Tumor DNA. Clinical Cancer Research : An Official Journal Of The American Association For Cancer Research 2018, 24: 1872-1880. PMID: 29330207, PMCID: PMC5899677, DOI: 10.1158/1078-0432.CCR-17-1341.
- A novel multiple biomarker panel for the early detection of high-grade serous ovarian carcinoma.Han C, Bellone S, Siegel ER, Altwerger G, Menderes G, Bonazzoli E, Egawa-Takata T, Pettinella F, Bianchi A, Riccio F, Zammataro L, Yadav G, Marto JA, Penet MF, Levine DA, Drapkin R, Patel A, Litkouhi B, Ratner E, Silasi DA, Huang GS, Azodi M, Schwartz PE, Santin AD. A novel multiple biomarker panel for the early detection of high-grade serous ovarian carcinoma. Gynecologic Oncology 2018, 149: 585-591. PMID: 29572027, PMCID: PMC5986604, DOI: 10.1016/j.ygyno.2018.03.050.
- Oligosaccharyltransferase Inhibition Overcomes Therapeutic Resistance to EGFR Tyrosine Kinase Inhibitors.Lopez Sambrooks C, Baro M, Quijano A, Narayan A, Wei C, Greninger P, Egan RK, Patel AA, Benes CH, Saltzman WM, Contessa JN. Oligosaccharyltransferase Inhibition Overcomes Therapeutic Resistance to EGFR Tyrosine Kinase Inhibitors. Cancer Research 2018, 78: 5094-5106. PMID: 30026325, PMCID: PMC6125176, DOI: 10.1158/0008-5472.CAN-18-0505.
- Monitoring immunotherapy outcomes with circulating tumor DNA.Goldberg SB, Patel AA. Monitoring immunotherapy outcomes with circulating tumor DNA. Immunotherapy 2018, 10: 1023-1025. PMID: 30185140, DOI: 10.2217/imt-2018-0084.
- Multiplexed enrichment of rare DNA variants via sequence-selective and temperature-robust amplification.Wu LR, Chen SX, Wu Y, Patel AA, Zhang DY. Multiplexed enrichment of rare DNA variants via sequence-selective and temperature-robust amplification. Nature Biomedical Engineering 2017, 1: 714-723. PMID: 29805844, PMCID: PMC5969535, DOI: 10.1038/s41551-017-0126-5.
- High-throughput RNA profiling via up-front sample parallelization.Narayan A, Bommakanti A, Patel AA. High-throughput RNA profiling via up-front sample parallelization. Nature Methods 2015, 12: 343-6. PMID: 25730493, PMCID: PMC4451056, DOI: 10.1038/nmeth.3311.
- Ultrasensitive measurement of hotspot mutations in tumor DNA in blood using error-suppressed multiplexed deep sequencing.Narayan A, Carriero NJ, Gettinger SN, Kluytenaar J, Kozak KR, Yock TI, Muscato NE, Ugarelli P, Decker RH, Patel AA. Ultrasensitive measurement of hotspot mutations in tumor DNA in blood using error-suppressed multiplexed deep sequencing. Cancer Research 2012, 72: 3492-8. PMID: 22581825, PMCID: PMC3426449, DOI: 10.1158/0008-5472.CAN-11-4037.
- Implications of respiratory motion as measured by four-dimensional computed tomography for radiation treatment planning of esophageal cancer.Patel AA, Wolfgang JA, Niemierko A, Hong TS, Yock T, Choi NC. Implications of respiratory motion as measured by four-dimensional computed tomography for radiation treatment planning of esophageal cancer. International Journal Of Radiation Oncology, Biology, Physics 2009, 74: 290-6. PMID: 19362248, DOI: 10.1016/j.ijrobp.2008.12.060.
- PSA failure following definitive treatment of prostate cancer having biopsy Gleason score 7 with tertiary grade 5.Patel AA, Chen MH, Renshaw AA, D'Amico AV. PSA failure following definitive treatment of prostate cancer having biopsy Gleason score 7 with tertiary grade 5. JAMA 2007, 298: 1533-8. PMID: 17911498, DOI: 10.1001/jama.298.13.1533.
- Estimation of the delivered patient dose in lung IMRT treatment based on deformable registration of 4D-CT data and Monte Carlo simulations.Flampouri S, Jiang SB, Sharp GC, Wolfgang J, Patel AA, Choi NC. Estimation of the delivered patient dose in lung IMRT treatment based on deformable registration of 4D-CT data and Monte Carlo simulations. Physics In Medicine And Biology 2006, 51: 2763-79. PMID: 16723765, DOI: 10.1088/0031-9155/51/11/006.
- Splicing double: insights from the second spliceosome.Patel AA, Steitz JA. Splicing double: insights from the second spliceosome. Nature Reviews. Molecular Cell Biology 2003, 4: 960-70. PMID: 14685174, DOI: 10.1038/nrm1259.
- The splicing of U12-type introns can be a rate-limiting step in gene expression.Patel AA, McCarthy M, Steitz JA. The splicing of U12-type introns can be a rate-limiting step in gene expression. The EMBO Journal 2002, 21: 3804-15. PMID: 12110592, PMCID: PMC126102, DOI: 10.1093/emboj/cdf297.