Page 52 - TD-3-4

Tumor Discovery PPAR agonist and cancer

is being evaluated alongside paclitaxel in a Phase I PPAR complex. In this context, fenofibrate increases fatty
trial for the treatment of anaplastic thyroid cancer, acid oxidation and mitochondrial respiratory capacity in
based on preclinical research showing that the drug CD8+ T lymphocytes, which enhances antitumor immunity
inhibits cell proliferation by upregulating RhoB and when combined with PD-1 blockade. TZDs have also
106
p21 while promoting apoptosis. 73,95,96 In patients with been shown to inhibit TGF-β transcription, resulting
advanced solid tumors, efatutazone has demonstrated in a significant reduction of the malignant phenotype
acceptable safety, tolerability, and disease control in gliomas. 107,108 In addition, inhibiting TGF-β signaling
when administered orally. In Japanese patients with improves survival and restores immune surveillance. 109
97
metastatic colorectal cancer, efatutazone combined
with FOLFIRI (5-fluorouracil, levoleucovorin, and 4.8. PPAR agonists for altering tumor
irinotecan) showed an acceptable safety profile and microenvironment
evidence of disease stabilization. For patients with The PPAR subtypes may function differently depending
98
high-grade gliomas (glioblastoma or anaplastic on the type of cancer and the stage of the tumor. In
glioma), a Phase II trial was initiated to examine the addition, the effects of PPAR agonists can vary based
efficacy of continuously administered pioglitazone and on the tumor microenvironment. For instance, the
rofecoxib in combination with low-dose chemotherapy expression of PPAR-γ in breast cancer cells inhibits
(capecitabine or temozolomide). The study indicated the NF-κB signaling pathway, reducing the levels of
that this novel regimen is well-tolerated and moderately proinflammatory, proangiogenic, and protransfer
effective. Patients with advanced vascular malignancies signaling molecules in the tumor microenvironment,
99
participated in a pilot study assessing the effectiveness including IL-6, IL-8, CXCR4, MMP-2, and MMP-9. This
of metronomically scheduled, low-dose trofosfamide in reduction inhibits tumor cell activity in breast cancer. 110,111
combination with pioglitazone and rofecoxib, a selective Tumor-associated macrophages (TAMs) are the most
COX-2 inhibitor, which may offer a new alternative for prevalent immune cells that promote neovascularization,
palliative care. A Phase II trial was initiated to analyze immunosuppression, and chemoresistance within
100
the effectiveness of pioglitazone and rofecoxib combined the tumor microenvironment. The activation of
112
with sequentially added angiostatic chemotherapy for PPAR-γ leads to lipid retention and PGE2 secretion,
patients with previously treated metastatic melanoma or which causes macrophage polarization toward anti-
soft-tissue sarcoma. This study demonstrated a novel and inflammatory TAMs, converting the M1 phenotype into
entirely orally administered chemotherapeutic regimen the M2 phenotype and diminishing the Stat3-mediated
that is well tolerated in patients with chemotherapeutic proinflammatory response. 113-116 In contrast, PPAR-α in
malignancies. 101 the tumor microenvironment often negatively affects
immune cells, leading to immunosuppression or cancer
4.7. PPAR agonists as a supportive regimen for immune escape. Tumor-derived exosomes substantially
cancer immunotherapy activate PPAR-α in tumor-infiltrating dendritic cells,
Immunotherapy has transformed cancer treatment in recent increasing intracellular lipid content and mitochondrial
decades by modifying immune responses against tumor respiration, which triggers cytotoxic T-cell activation and
cells to enhance the effectiveness of conventional therapies immune dysfunction. Cancer stem cells (CSCs) are
117
such as chemotherapy and radiation. Programmed cell frequently associated with the development of malignant
118
death protein 1 (PD-1) is a receptor present on immune tumors. Stearoyl-CoA desaturase 1 is an ER enzyme that
cells that plays a crucial role in regulating the immune converts saturated fatty acids into monounsaturated fatty
response. PD-1 restricts the entry and survival of T cells acids. PPAR-α activates the stearoyl-CoA desaturase 1
119
within the tumor microenvironment. However, targeting pathway, which is significantly upregulated to maintain
PD-1 with inhibitors allows T cells to infiltrate the tumor, CSC stemness in human liver cancer. Cells in the tumor
120
thereby enhancing the effects of other cancer therapies. 102-104 microenvironment exhibit increased glucose uptake
PPAR agonists are a promising adjunct to immunotherapy, and glycolysis, enhanced glutamine depletion, and the
as they can boost the antitumor activity of T cells, even dissolution of carbon and amino nitrogen. This becomes
in an immunosuppressive tumor microenvironment. a direct source of energy for the cancer cells. 120-122 PPARs
Research has shown that fenofibrate, an agonist of PPAR-α, are known regulators of cellular metabolism, particularly
can work synergistically with PD-1 blockers in cancer carbohydrate and mitochondrial-linked metabolism.
immunotherapy by altering the metabolism of effector Thus, altering PPAR activity through their antagonists can
T cells. PD-1 blockade has also been found to work in modify the metabolism of cancer cells, which is related to
105
conjunction with bezafibrate, an agonist of the PGC-1α/ the Warburg effect. 123-125

Volume 3 Issue 4 (2024) 9 doi: 10.36922/td.4003