Drug and Oncogene Information

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Update: “2024-06-17”



Drug Information

This is the list of drugs that I have analyzed testing data of in DFCI.

Drug Target/Mechanism Clinical Applications Development Stage Company Sources
DGKi Inhibits diacylglycerol kinase, enhancing T-cell activation and immune responses by modulating DAG and PA signaling pathways. Explored for potential application in enhancing the efficacy of cancer immunotherapies by boosting T-cell functionality. Preclinical/early clinical trials Bristol Myers Squibb Nature Review on DGK inhibitors
DS-1062a TROP2-targeting antibody-drug conjugate with a cytotoxic topoisomerase I inhibitor payload (deruxtecan). Targeted therapy for TROP2-expressing tumors, including non-small cell lung cancer and triple-negative breast cancer. Phase II/III clinical trials Daiichi Sankyo Daiichi Sankyo’s Pipeline
TAK-676 Synthetic cyclic dinucleotide that acts as a STING agonist to activate the innate immune system. Enhancing the effectiveness of existing cancer therapies by promoting immune cell infiltration and activation in tumors. Phase I/II clinical trials Takeda Pharmaceuticals ClinicalTrials.gov Entry for TAK-676
ADU-S100 Synthetic cyclic dinucleotide STING agonist that stimulates type I interferon and pro-inflammatory cytokine production. Used in combination with immune checkpoint inhibitors to treat advanced solid tumors and cutaneous malignancies. Phase I/II clinical trials Aduro Biotech, Novartis Aduro’s ADU-S100 Information



Detailed Functions

DGKi:
- DGKi targets diacylglycerol kinase, an enzyme that regulates T-cell activation by modulating the levels of diacylglycerol (DAG) and phosphatidic acid (PA) within cells. Inhibition of this enzyme prevents the conversion of DAG to PA, thereby maintaining DAG levels that are crucial for downstream signaling events following T-cell receptor engagement. This mechanism is believed to potentiate the immune response by enhancing T-cell activation, proliferation, and survival, making it a valuable target for boosting the effectiveness of T-cell-based cancer immunotherapies.

DS-1062a:
- DS-1062a is designed to selectively target and kill TROP2-expressing tumor cells. Its mechanism involves the targeted delivery of a potent cytotoxic drug directly to the tumor cells, minimizing the impact on non-targeted cells. This targeted approach allows for higher drug concentrations at the tumor site, increasing tumor cell death while reducing systemic toxicity. The ADC mechanism of DS-1062a utilizes the internalization of the TROP2 antibody bound to its antigen on cancer cells, followed by the intracellular release of the cytotoxic payload that induces DNA damage and cell death.

TAK-676:
- TAK-676 utilizes the STING (Stimulator of Interferon Genes) pathway to initiate and amplify the immune response against cancer cells. By activating STING, TAK-676 triggers a cascade of signaling events that lead to the production of type I interferons and other cytokines, which enhance the body’s ability to detect and destroy cancer cells. This activation is crucial for recruiting and activating immune cells, including T cells and NK cells, into the tumor microenvironment, thereby improving the overall effectiveness of cancer immunotherapies.

ADU-S100:
- ADU-S100 works by targeting the STING pathway, which plays a pivotal role in the innate immune system’s ability to detect and respond to the presence of tumor-derived or pathogen-derived cytosolic DNA. Activation of this pathway by ADU-S100 leads to the induction of a strong inflammatory response that promotes the activation and recruitment of dendritic cells and T cells, key players in the adaptive immune response. This mechanism enhances the visibility of tumors to the immune system and facilitates the establishment of an effective anti-tumor immune response, especially when used in combination with other therapies that modulate the immune environment.




Combinational drug theraphy expectations

Pembrolizumab (Keytruda)

Mechanism of Action:

Clinical Applications:

Nivolumab (Opdivo)

Mechanism of Action:

Clinical Applications:

Pembrolizumab or Nivolumab Combined with DGKi

Advantages:

  1. Enhanced T-cell Activation: DGKi enhances T-cell activation by modulating DAG and PA signaling pathways. This could potentially synergize with Pembrolizumab or Nivolumab, which release the brakes on T-cells by blocking PD-1, leading to a more robust anti-tumor response.
  2. Improved Efficacy: Combining two different mechanisms to stimulate T-cells could increase the overall efficacy of the immune response against tumors.

Disadvantages:

  1. Increased Immune-Related Adverse Events (irAEs): Both PD-1 inhibitors and DGKi can enhance immune responses, which might lead to a higher risk of autoimmune reactions and other immune-related adverse events.
  2. Complex Management: The combination may require careful monitoring and management of side effects, which could complicate treatment protocols.

Pembrolizumab or Nivolumab Combined with DS-1062a

Advantages:

  1. Targeted Cytotoxicity: DS-1062a targets TROP2-expressing tumors, delivering a cytotoxic payload directly to cancer cells. When combined with Pembrolizumab or Nivolumab, this approach could enhance the immune system’s ability to attack cancer cells while simultaneously delivering a lethal blow to the tumor.
  2. Broadened Applicability: This combination could be effective in TROP2-expressing tumors that may not respond well to PD-1 inhibitors alone.

Disadvantages:

  1. Overlapping Toxicities: Both treatments can cause specific side effects, and when combined, there might be an increase in overlapping toxicities, such as fatigue, nausea, and potential immune-related issues.
  2. Treatment Complexity: Administering an antibody-drug conjugate (ADC) alongside a PD-1 inhibitor could increase the complexity of the treatment regimen.

Pembrolizumab or Nivolumab Combined with TAK-676

Advantages:

  1. Enhanced Immune Activation: TAK-676, a STING agonist, activates the innate immune system, leading to increased production of type I interferons and cytokines. This could enhance the effectiveness of Pembrolizumab or Nivolumab by further stimulating an immune response against the tumor.
  2. Synergistic Effects: The combination could potentially lead to a stronger and more sustained anti-tumor response by activating both the innate and adaptive immune systems.

Disadvantages:

  1. Increased Risk of Inflammation: Both STING agonists and PD-1 inhibitors can cause inflammation. Combined use might increase the risk of severe inflammatory responses, necessitating careful patient monitoring.
  2. Potential Redundancy: There may be cases where the activation of the immune system by TAK-676 does not significantly add to the effect already achieved by PD-1 inhibition.

DS-1062a

Component of DS-1062a

TROP2

Dxd

DS-1062a

Datopotamab Deruxtecan (NCI Info)

  1. Antibody-Drug Conjugate (ADC) :
    • Humanized monoclonal antibody against TAA TROP2 (TACSTD2).
    • Enzymatically cleavable tetrapeptide-based linker.
    • Cytotoxic DNA topoisomerase I inhibitor and exatecan (DX-8951) derivative DXd (MAAA-1181a; MAAA-1181).
  2. Mechanism:
    • Anti-TROP2 antibody targets and binds to TROP2 on tumor cells.
    • Cellular uptake and lysosomal degradation of the linker.
    • DXd targets and binds to DNA topoisomerase I.
    • Stabilizes the cleavable complex between topoisomerase I and DNA.
    • Results in DNA breaks, inhibition of DNA replication, and apoptosis.
    • Inhibits tumor cell proliferation of TROP2-expressing tumor cells.
  3. TROP2 Featuures:
    • Transmembrane protein overexpressed in various tumors.
    • Low and/or restricted expression in normal, healthy tissues.
    • Associated with enhanced tumor aggressiveness, metastasis, drug resistance, and increased tumor cell survival.
  4. ADC Advantages:
    • Reduced systemic exposure.
    • Enhanced delivery of the cytotoxic agent DXd.