Abstract 3606: Blockade of the PPARα metabolic checkpoint with TPST-1120 suppresses tumor growth and stimulates anti-tumor immunity
Bibliographic record
Abstract
Abstract Tumors evolve to modulate metabolism to promote their own survival and to suppress tumor-specific immunity. Hypoxic conditions in the tumor microenvironment (TME) induce fatty acid oxidation (FAO), and diverse malignancies are reliant on this metabolic pathway. Additionally, suppressive immune cell populations including M2 macrophages, myeloid-derived suppressor cells and regulatory T cells preferentially utilize FAO. Peroxisome proliferator-activated receptor alpha (PPARα) is the principal transcription factor that regulates the expression of FAO genes, and this metabolic checkpoint is critical for tumor proliferation. TPST1120 is a first-in-class selective competitive antagonist of the human PPARα. To test the hypothesis that blocking FAO with TPST-1120 confers anti-tumor efficacy, we assessed TPST-1120 in multiple syngeneic and xenograft mouse models. Blockade of PPARα with TPST-1120 mediated potent anti-tumor immune responses and significant tumor regression in syngeneic models of breast, lung, colon, pancreatic and melanoma in addition to xenograft models of CLL, AML, pancreatic and melanoma cancers as a monotherapy or in combination with chemotherapy. In pancreatic and breast cancer models, TPST-1120 augmented regression of tumor growth in combination with chemotherapy. In combination with anti-PD1, TPST-1120 treatment resulted in significant reduction of tumor growth in ovarian orthotopic (ID8) and colon (MC38) models; cured mice were completely protected against autologous tumor challenge, strongly suggesting immunological T cell memory against the primary tumor. Studies in genetic knock-out mice indicated that macrophages and antigen cross-presenting dendritic cells are required for TPST-1120 activity, mediated through thrombospondin-1(TSP-1) and stimulator of interferon genes (STING). Consistent with prior reports, inhibition of PPARα with TPST-1120 skewed macrophages in vivo toward an M1 effector phenotype. These results provide the rationale for evaluating TPST-1120 in patients with advanced malignancies. A Phase 1/1b open-label, dose-escalation and dose-expansion study of TPST-1120 as a single agent or in combination with systemic anti-cancer therapies is planned in early 2019. Citation Format: Chan C. Whiting, Nick Stock, Davorka Messmer, Traci Olafson, Derek Metzger, Amanda Enstrom, Jennifer McDevitt, David Spaner, Peppi Prasit, Dipak Panigrahy, Ginna Laport. Blockade of the PPARα metabolic checkpoint with TPST-1120 suppresses tumor growth and stimulates anti-tumor immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3606.
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.002 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".