SARAH

Background and Rationale:
Clonal hematopoiesis of indeterminate potential (CHIP) is frequently observed in older individuals, where hematopoietic stem cells acquire mutations in genes like TET2 or JAK2. TET2 mutations lead to epigenetic dysregulation, while JAK2 mutations cause persistent JAK/STAT signaling. These mutations drive clonal expansion of lymphoid and myeloid cells without overt hematologic malignancy. Preliminary data suggest CHIP promotes the development and progression of solid tumors, including NSCLC and pancreatic carcinoma, likely through deregulated inflammatory signaling. However, the underlying cellular mechanisms and the critical molecular events remain unknown. This proposal aims to close this knowledge gap by elucidating CHIP’s role in tumorigenesis and to develop therapies targeting CHIP in cancer patients.

Hypothesis:
CHIP mutations in hematopoietic stem cells, particularly in TET2 and JAK2, create a pro-inflammatory environment by increasing cytokines like IL-6, IL-1ß, and TNF-a. This chronic inflammation promotes tumorigenesis, enhancing cancer cell proliferation, survival, angiogenesis, and metastasis. CHIP also alters immune surveillance, leading to immune exhaustion and reduced efficacy of checkpoint inhibitors. We hypothesize therefore that by targeting CHIP-associated inflammation and immune dysregulation we can directly affect cancer cells and improve therapy outcomes. We posit further that we can achieve this by interfering with the kinase JAK2, the epigenetic regulator LSD1 and its associated transcription factor GFI1, which all play a critical role in the regulation of CHIP associated pro-inflammatory processes.

Aims:
1. Demonstrate that targeting CHIP-related immune alterations improves cancer therapy outcomes.
2. Investigate how CHIP-associated macrophages and other immune cells alter cancer cell physiology using experimental animal models and patient samples.
3. Identify drugs targeting CHIP-induced inflammation that act synergistically with standard anti-cancer treatments, focusing on inhibitors of the enzymes LSD1 and JAK2, which are both linked to the emergence of CHIP.

Methods:
We will study CHIP-associated immune cells, including macrophages, T cells, and neutrophils, using murine models, ex vivo systems, and primary patient samples. Complementary screening approaches will test the efficacy of LSD1 and JAK2 inhibitors, alone or combined with other drugs, to enhance established therapies by targeting CHIP-driven inflammation.

Expected Results and Impact:
We expect to model CHIP in mice and human cell systems, clarifying its role in cancer progression and therapy response. We anticipate demonstrating that targeting CHIP with LSD1 or JAK2 inhibitors, combined with anti-tumor treatments, can significantly improve outcomes for patients with NSCLC and pancreatic carcinoma, which are deadly diseases and presently have very poor prognosis.