Friday, December 1, 2023 12/1/2023

Developing Bioinformatic and Microfluidic Single Cell Methods for Studying Intratumoral Heterogeneity in Acute Myeloid Leukemia

Award Number: R01CA226172
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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PROJECT SUMMARY/ABSTRACT It has been hypothesized that chemotherapy resistance reflects selection for a mutant clone of tumor cells that is intrinsically resistant to chemotherapy due to its unique genetics. However, recent reports demonstrate only a weak correlation between acute myeloid leukemia genotype and chemotherapy resistance. As an alternative, we propose that intratumoral heterogeneity (ITH, i.e. clonal diversity) may be a predictor of chemotherapy resistance. While one might hypothesize that increased levels of ITH relates to less tractable disease, little data is available that definitively links ITH with outcome, let alone a relationship between the presence of genetic diversity and gene expression or other phenotypic changes. While the role of clonal evolution during leukemia development and therapy has been a focus for a number of avenues of research, the ability to deduce the clonal composition of individual samples has been limited by the use of data from bulk tumor samples. Many of the genetic assessments of clonality performed on cancer specimens will require the final description of clonality to be informed by single cell data rather than solely relying on computational deconvolution of the clonal structure. Unfortunately, despite sequencing cost reductions, the challenge of generating statistically meaningful data from single cells makes most techniques not cost effective or flat out uninformative for this purpose. Beyond the costs, the enormous technical and computational challenges that exist for generating and analyzing the data limit single cell analysis to research laboratories often not involved with clinical research. Refining the technical ability to derive accurate data at the bulk and single cell levels, appropriately process and interpret these data, and apply this approach to larger cohorts of patients are crucial next steps for making relevant biological conclusions from ITH analyses. We aim to address this challenge by combining bulk- level ITH deconvolution with single cell targeted genetic analysis using our novel microfluidic chip, and extending this technique to include downstream transcriptomic assessments. The ability to identify genetic diversity, track it through therapy, and connect this diversity with corresponding gene expression changes would all provide a substantial improvement in our clinical understanding of the role of ITH in cancer therapy. With the possibility to more directly query the genetic variability and possible transcriptomic implications of this in both model systems as well as in primary human specimens, we can more clearly understand what role intratumoral heterogeneity plays in human malignancy. Alternative therapies designed to level the evolutionary playing field for all clones and reduce their frequency to a manageable level, could essentially transform an acute disease to a chronic one. This possibility would be a valuable new clinical option for especially toxic, or poorly tolerated therapies designed to abolish all clones that often result in more aggressive relapsed disease.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2023 ( Subtotal = $614,764 )
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Detection and Diagnosis Research	001	6	3/14/2023	NON-COMPETING CONTINUATION	$50,185
2023	2023	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Detection and Diagnosis Research	000	6	11/23/2022	NON-COMPETING CONTINUATION	$564,579


Issue Date FY: 2022 ( Subtotal = $614,764 )
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Detection and Diagnosis Research	005	4	8/10/2022	NON-COMPETING CONTINUATION	-$134,571
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Detection and Diagnosis Research	006	5	8/10/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$141,764
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Detection and Diagnosis Research	000	4	11/30/2021	NON-COMPETING CONTINUATION	$564,579
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Detection and Diagnosis Research	002	5	5/31/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$430,008
2022	2022	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Detection and Diagnosis Research	001	4	5/31/2022	NON-COMPETING CONTINUATION	-$430,008
2022	2022	FRED HUTCHINSON CANCER CENTER	1100 FAIRVIEW AVE N	SEATTLE	WA	98109	KING	USA	Cancer Detection and Diagnosis Research	003	5	6/14/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$50,185
2022	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Detection and Diagnosis Research	004	3	8/10/2022	NON-COMPETING CONTINUATION	-$7,193


Issue Date FY: 2021 ( Subtotal = $377,311 )
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Detection and Diagnosis Research	001	3	1/22/2021	NON-COMPETING CONTINUATION	$9,066
2021	2021	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Detection and Diagnosis Research	000	3	11/27/2020	NON-COMPETING CONTINUATION	$368,245


Issue Date FY: 2020 ( Subtotal = $615,257 )
2020	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Detection and Diagnosis Research	002	2	1/14/2020	NON-COMPETING CONTINUATION	$61,525
2020	2020	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Detection and Diagnosis Research	001	2	11/20/2019	NON-COMPETING CONTINUATION	$553,732
2020	2019	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Detection and Diagnosis Research	000	1	11/15/2019	NEW	$0


Issue Date FY: 2019 ( Subtotal = $634,257 )
2019	2019	FRED HUTCHINSON CANCER RESEARCH CENTER	1100 FAIRVIEW AVE N J6-300	SEATTLE	WA	98109	KING	USA	Cancer Detection and Diagnosis Research	000	1	12/10/2018	NEW	$634,257


Grand Total All Awards = $2,856,353

Sum of Action Amount is $2,856,353;

Grand Total = $2,856,353

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Developing Bioinformatic and Microfluidic Single Cell Methods for Studying Intratumoral Heterogeneity in Acute Myeloid Leukemia

Award Number: R01CA226172

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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