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Targeting altered phosphatase-dependent signaling to overcome the inefficacy of targeted therapy in myeloproliferative neoplasms

Award Number: R01HL151579
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Targeting altered phosphatase-dependent signaling to overcome the inefficacy of targeted therapy in myeloproliferative neoplasms - Project Summary/Abstract Classical myeloproliferative neoplasms (MPNs) are blood disorders that affect about 300,000 people in the U.S. Blood clotting complications and bone marrow failure can cause death, as can the development of an incurable leukemia. Curative therapy by stem cell transplant is rarely possible. Aberrant regulation of a protein called JAK2 drives these disorders, and while JAK2 inhibitors improve MPN patient symptoms they do not induce remission, with inherent drug resistance being a major clinical bottleneck. Our recent studies suggest a protein called SHP2 plays a unique role in the response of MPN cells to the FDA-approved JAK inhibitor ruxolitinib. Therapeutically targeting SHP2 is now possible following the recent development of drugs that function as molecular glue to keep SHP2 stuck in an inactive state. The upfront survival of MPN cells in the face of ruxolitinib treatment is a form of drug resistance called persistence. Our current studies show that ruxolitinib persistent cells are more sensitive to SHP2 inhibition than cells that have never been exposed to ruxolitinib. In the latter cells ruxolitinib inhibits JAK2-dependent signals including STAT and ERK proteins. However, ERK rapidly becomes re-activated even while ruxolitinib is still present. We have observed that SHP2 inhibition blocks this re-activation of ERK. Since ERK can promote cell growth/survival, it is possible that altered SHP2 regulation during ruxolitinib treatment leads to cell survival. Interestingly, the activation states of proteins that mediate JAK2 signaling respond differently to SHP2 inhibition in persistent cells, suggesting cell signaling during ruxolitinib persistence is in a re-wired state. This may explain our observations that SHP2 inhibition can prevent a ruxolitinib persistent state. Thus, SHP2 may provide a vulnerability that can be exploited to improve MPN therapy, which is further supported by our observations that SHP2 inhibition can antagonize disease in an MPN mouse model and can improve the inhibitory effect of ruxolitinib on cells from MPN patients. The major objective of this application is to determine the extent to which SHP2 inhibition overcomes barriers of current anti-JAK2 MPN therapy. The central hypothesis is that targeting SHP2 will thwart the development of JAK2 inhibitor persistence, which is observed in MPN patients. We will utilize cellular, genetic, and biological approaches, including mouse models and cells from MPN patients in our studies. Experiments in aim 1 will determine mechanistic details by which SHP2 inhibition sensitizes MPN cells to JAK2 inhibition; in aim 2 will assess the role of SHP2 in drug persistence; and in aim 3 will determine the molecular basis/consequences of altered SHP2 signaling in response to ruxolitinib, which has potential to help develop new therapeutic approaches based on our novel observations. Our studies are innovative because the unique role of SHP2 in response to JAK2 inhibitor treatment is completely unknown and utilizing SHP2 as a therapeutic target in these MPNs has never been tested. Our studies could contribute to the development of effective therapies for the 300,000 people in the U.S. who suffer with an MPN.


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: 2024 ( Subtotal = $464,330 )
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Blood Diseases and Resources Research	000	4	1/15/2024	NON-COMPETING CONTINUATION	$426,425
2024	2024	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 USF MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Blood Diseases and Resources Research	001	4	6/21/2024	NON-COMPETING CONTINUATION	$37,905
														Subtotal = $464,330

Issue Date FY: 2023 ( Subtotal = $477,968 )
2023	2023	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Blood Diseases and Resources Research	000	3	2/15/2023	NON-COMPETING CONTINUATION	$477,968
														Subtotal = $477,968

Issue Date FY: 2022 ( Subtotal = $483,261 )
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Blood Diseases and Resources Research	000	2	2/2/2022	NON-COMPETING CONTINUATION	$434,933
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Blood Diseases and Resources Research	002	2	6/8/2022	NON-COMPETING CONTINUATION	$48,329
2022	2022	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Blood Diseases and Resources Research	001	2	2/17/2022	NON-COMPETING CONTINUATION	-$1
														Subtotal = $483,261

Issue Date FY: 2021 ( Subtotal = $485,801 )
2021	2021	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Blood Diseases and Resources Research	001	1	6/23/2021	NEW	$48,580
2021	2021	H. LEE MOFFITT CANCER CENTER AND RESEARCH INSTITUTE HOSPITAL, INC.	12902 MAGNOLIA DR	TAMPA	FL	33612	HILLSBOROUGH	USA	Blood Diseases and Resources Research	000	1	2/3/2021	NEW	$437,221
														Subtotal = $485,801

Grand Total All Awards = $1,911,360

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Targeting altered phosphatase-dependent signaling to overcome the inefficacy of targeted therapy in myeloproliferative neoplasms

Award Number: R01HL151579

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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