The Science Behind Califia Pharma: TCR Inhibition
Califia Pharma’s innovative approach to treating drug-resistant metastatic cancer is presented in numerous publications and presentations.
The publications marked with an asterisk “*” are authored by Dr. Kelner
Publications
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* Preclinical evaluations of Illudins as anticancer agents. Cancer Research, 1987
* Structure and reactivity of Illudins. Tetrahedron, 1989
* Characterization of cellular accumulation and toxicity of Illudin S in sensitive and non-sensitive tumor cells. Cancer Chemother Pharmacol, 1997
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* Characterization of Illudin S sensitivity of DNA repair-deficient Chinese Hamster cells. Biochem. Pharmacol, 1994
* Efficacy of MGI 114 (HMAF) against the mdr1/gp170 metastatic MV522 lung cancer xenograft. Eur. J. Cancer, 1998
* Efficacy of MGI 114 against the MRP-positive metastatic MV522 lung carcinoma xenograft. Anti-Cancer Drugs, 2000
Modulation of cytotoxicity by transcription-coupled nucleotide excision repair is independent of the requirement for bioactivation of acylfulvene. Chem Res Toxicol, 2017
Mechanism of RNA polymerase II stalling by DNA alkylation. Proc. Natl. Acad. Sci. USA, 2017
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* Acylfulvenes, a new class of potent antitumor agents. Experientia, 1996
* Design and synthesis of antitumor Acylfulvenes. J Org Chem, 1997
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* Efficacy of HMAF (MGI-114) in the MV522 metastatic lung carcinoma xenograft model nonresponsive to traditional anticancer agents. Invest. New Drugs, 1996
* (Hydroxymethyl)acylfulvene: an Illudin derivative with superior antitumor properties J. Natural Products, 1996
* Total synthesis of Hydroxymethylacylfulvene; an antitumor derivative of Illudin S. Chem. Commun, 1997.
* Metabolism of antitumor Acylfulvene by rat liver cytosol. Biochem. Pharmacol. 1999.
* Characterization of MGI 114 (HMAF): Histiospecific toxicity in human tumor cell lines. Drug Metab. Dispos. 1999
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* Anti-leukemic action of the novel agent MGI 114 (HMAF) and synergistic action with Topotecan. Leukemia, 2000
* Enhanced antitumor activity of irofulven in combination with thiotepa or mitomycin C. Cancer Chemother. Pharmacol. 2002
* Enhanced antitumor activity of Irofulven in combination with antimitotic agents. Invest New Drugs, 2002.
* Synergy of Irofulven in combination with various anti-metabolites, enzyme inhibitors, and miscellaneous agents in MV522 lung carcinoma cells: marked interaction with gemcitabine and 5-fluorouracil. Invest. New Drugs, 2008
* Synergy of Irofulven in combination with other DNA damaging Agents: synergistic interaction with altretamine, alkylating, and platinum-derived agents in the MV522 lung tumor model. Cancer Chemotherap Pharmacol, 2008
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* Structure activity-relationships of Illudins Analogs with improved therapeutic index. J. Org. Chem., 1992
* Preparation and biological activity of amino acid and peptide conjugates of antitumor hydroxymethylacylfulvene. J. Med. Chem., 2000.
* Structure-activity studies of antitumor agent irofulven (hydroxymethylacylfulvene) and analogues. J. Org. Chem., 2001
* Structure-activity relationship studies of Illudins: Analogues possessing a spiro-cyclobutane ring. J. Org. Chem., 2003
* Synthesis and biological activity of enantiomers of antitumor Irofulven. J. Org. Chem, 2004
* Synthesis and Antitumor Activity of Amine Analogs of Irofulven. Bioorganic & Medicinal Chemistry Letters, 2007
* Structure-Activity Studies of Urea, Carbamate and Sulfonamide Derivatives of Acylfulvene. J. Med. Chem., 2010
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* Preclinical evaluation of CAP-0121 for multidrug resistant cancers. Proc American Assoc Cancer Res, 2022.
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These external studies provide:
• Confirmation of the incidence of TCR-deficient cancers (ERCC2 or ERCC3) in breast, bladder and renal cancer and that these cancers are easily detected at an academic oncology center.
• Confirmation that these TCR-deficient cancers express high levels of PTGR1 and are extremely sensitive to Illudofulvenes (including xenograft studies).
• Confirmation that pharmacologically achievable first-generation drug levels achieved in humans are sufficient for killing TCR-deficient human cancers (based on 1 hour AUC).
Targeting Germline- and Tumor-Associated Nucleotide Excision Repair Defects in Cancer. Clin Cancer Res, 2021
Identification of a Synthetic Lethal Relationship between Nucleotide Excision Repair Deficiency and Irofulven Sensitivity in Urothelial Cancer. Clin Cancer Res, 2021
Nucleotide excision repair deficiency is a targetable therapeutic vulnerability in clear cell renal cell carcinoma. BioRxiv, 2023
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Editorial: Morning for Irofulven, What could be fiNER? Clin Cancer Res, 2021
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A genetic map of the response to DNA damage in human cells. Cell, 2020
The UVSSA protein is part of a genome integrity homeostasis network with links to transcription- coupled DNA repair and ATM signaling. Proc Natl Acad Sci USA, 2022.
Elongation factor ELOF1 drives transcription-coupled repair and prevents genome instability. Nat Cell Biol., 2021.