Hot Topics in Preclinical and Clinical Research Notes

Precision Oncology

  • People die because they don't respond to treatment, sometimes because of genetic variability.
  • The goal is to detect cancer early for survival without invasive therapies.
  • Precision oncology involves sequencing a tumor's genome to identify mutated genes.
  • A compound is developed to target the mutated gene, attacking only cancer cells.
  • Drug repurposing: using existing drugs for new cancer treatments.
  • Need to consider past context to make informed decisions.
  • Chemotherapy in the 1930s was a one-drug-fits-all approach, leading to toxicity and low success rates.
  • Discovery of DNA and genetics revealed cancer heterogeneity.
  • Tumor biopsies are analyzed, but single biopsies are insufficient due to genetic variations within the tumor.
  • Cancer heterogeneity varies by tumor type.
  • Sequencing techniques can identify the tumor's specific characteristics.
  • Precision oncology aims to create drugs specific to the cancer cell phenotype.

Precision Medicine Trials: From First to Second Generation

  1. Volunteer participants with the condition are recruited (e.g., COVID-19).
  2. Participants are randomly assigned to a drug or usual care.
  3. Data is gathered from participants.
  4. Data is evaluated and compared to usual care results.
  5. Ineffective drugs are removed; effective drugs proceed for real-world use.

Clinical Trial Phases

  • Phase 1: Primarily assesses safety in healthy volunteers.
  • Phase 2 (including 2a and 2b): Focuses on dosage and efficacy in larger patient groups.
    • Phase 2a: Small cohort, exploratory, confirms safety.
    • Phase 2b: Larger cohort, confirms effectiveness.
  • Phase 3: Confirms effectiveness and monitors adverse effects across diverse populations before marketing approval.
  • Phase 4: Post-marketing surveillance to gather more data on the drug's effects in the general population.

Clinical Trial Designs

  • Platform Trial:
    • Open-ended question format.
    • Randomize participants into drug/control groups.
    • Collect and evaluate data, comparing it with usual care to make decisions.
    • New interventions (drugs) can be added, assessed, and removed over time.
    • Starts without pre-specifying potential new interventions.
    • Disease-focused rather than intervention-focused (identifying best drug for a disease rather than if a specific drug is better than placebo).
  • Umbrella Trial:
    • Assesses multiple drugs targeting different mutations within the same type of cancer.
    • Aims for quicker approval of drugs by authorities.
    • Tests new drugs or substances in patients with the same cancer type but different gene mutations or biomarkers.
    • Drugs being tested can change as new targets/drugs are identified.
  • Basket Trial:
    • Tests a specific drug that targets a particular mutation across different cancer types.
    • Patients with different cancer types but the same mutation receive the same treatment.
    • Useful for studying rare cancers and cancers with rare genetic changes; also called bucket trial.

Drug Development Process

  • Discovery Phase: Identifying a potential target.
  • Identifying a small molecule to specifically target the mutation.
  • Preclinical Phase.
  • Clinical Phase: After which the drug can go on the market (subject to regulatory agencies like AFMPS in Belgium).
  • Salami Slicing: Agencies establishing rules to expedite drug approval and support companies developing drugs for specific diseases.
  • Companies prioritize developing drugs for prevalent diseases to ensure a return on investment.

Incentives for Rare Disease Drug Development

  • Agencies define rare diseases by a specific number of affected individuals in a country.
  • Companies receive protection in terms of patents, financial aid, and selling advantages for developing drugs against rare diseases.
  • Precision medicine leads to numerous drugs for the same cancer type but for different mutations.
  • Companies may redefine particular subsets of cancer as rare diseases to capitalize on financial incentives.
  • Agencies have adjusted regulations to address this.

NCI-MATCH (Molecular Analysis for Therapy Choice)

  • Aims to analyze diseases and choose the right therapy.
  • NCI is the National Cancer Institute within the NIH.
  • Recruited 6000 patients in under two years, used NGS to characterize tumors.
  • 38% of screened patients had a potentially actionable mutation.
  • Observed low response rate to single agents.

Resistance to Targeted Therapies

  • Resistance to single targeted agents is attributed to multiple mechanisms, including resistance mutations and multigenic or adaptive responses.
  • The vision of precision medicine has evolved to address resistance pathways.
  • Starting point: observation with chemotherapeutic agents that kill all proliferating cells (causing toxicity).
  • The focus now is on resolving toxicity, resistance, and addressing cancer heterogeneity by attacking cancer cells in different ways.

NCI's New Trials Addressing Treatment Challenges

  1. ComboMATCH:
    • Tests molecularly targeted combinations to overcome primary and adaptive resistance pathways.
    • Evolved from original MATCH trial, assigning patients to single targeted therapies based on tumor genomics.
    • Focuses on combination treatments, targeting multiple cancer-driving pathways simultaneously.
    • Involves molecular profiling (e.g., next-generation sequencing) on patients' tumors.
    • Patients are matched to trials testing combinations of drugs based on genetic findings.
    • Requires testing combinations in two different in vivo models before phase 1 and 2 trials.
  2. iMATCH:
    • Aims to advance precision immunotherapy, particularly by identifying predictive biomarkers of response.
    • Focuses on solid tumors (e.g., lung cancer, melanoma) and their interaction with the immune system.
    • Involves in-depth profiling of the tumor microenvironment, including immune cell infiltration, PD-L1 expression, tumor mutational burden (TMB), etc.
    • Assigns patients to immunotherapy trials based on immune-related biomarkers.
    • Resensitizes tumors to the immune system.
    • Targets immune checkpoints (PD1 and PDL1).
    • PD-L1 on cancer cells binds to PD1 on lymphocytes, inhibiting them, so checkpoint inhibitors disrupt this ligation.
  3. MyeloMATCH:
    • Aims to personalize treatment for myeloid malignancies like acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS).
    • Focuses on cancers of the blood and bone marrow originating from the myeloid lineage.
    • Involves extensive genomic and molecular testing (e.g., FLT3, IDH1/2, NPM1 mutations).
    • Enrolls patients into adaptive clinical trial arms based on their specific molecular abnormalities.

Types of Resistance

  • Adaptative resistance: Cancer responds to treatment, the tumor shrinks, but residual cells proliferate once the pressure is not there and resurfaces with resistance. Patient is in remission.
  • Intrinseque resistance: Cancer has mutations or expresses resistance proteins that cause resistance to any treatment.

Multidrug Resistance in Cancer

  • Observed since the beginning of chemotherapy.
  • Cancer, not the patient, resists treatment.
  • Resistance exists against every effective anticancer drug.
  • Develops through multiple mechanisms and can affect single or multiple drugs.
  • Cells become resistant to structurally and mechanistically unrelated drugs, known as multidrug resistance.
  • Can be intrinsic or acquired.

Mechanisms of Multidrug Resistance

  1. Drug's Entry Into Tumor Cell:
    • Drug is chemotized by an enzyme group, then enters through passive diffusion, endocytosis, or transporters.
    • Uptake transporters (360 SLCs).
  2. Drug Metabolism Inside the Cell:
    • Drug binds to its target, leading to cell death.
    • Drug is metabolized in three phases: oxidation (CYP450), conjugation (sulfonation), and transport.
      • Phase 1: Oxidation (CYP450) creates reactive metabolites (epoxide group), neutralized by epoxide hydrolase.
      • Phase 2: Enzymes conjugate metabolites (sulfonation) to make the drug highly hydrophilic.
      • Efflux transporters (Non-ABC or ABC efflux transporters) eject metabolites.
  3. Sequestration:
    • Drug is scavenged by metallothioneins (MT) or sequestered in organelles (lysosomes).

Additional Factors in Drug Resistance

  • Manipulating proteins that mediate resistance is difficult.
  • Tumor Microenvironment (TME): Hypoxic and acidic TME impacts drug entry and modulates gene expression that mediates drug resistance.

Drug Efficiency and Resistance

  • Not 100% of the drug reaches its target.
  • Drug resistance may occur via efflux transporters, especially ABC transporters (48 ABCs).
  • Cancer mutations may affect uptake transporters.

Similarities Between Cancer and Drug Resistance Hallmarks

  • Malignantly transformed cells facilitate MDR mechanisms.
  • Altered cellular pharmacology (overexpression of ABC transporters).

ABC Transporters

  • Play an important role in multidrug resistance in cancer and in pathogens (resistance to antibiotics).
  • Expressed in plants and other microorganisms.
  • Important role in drug pharmacokinetics (uptake, distribution, and excretion) because they are expressed in the intestine, kidney, liver, and blood.
  • Important role in drug toxicity.
  • Markers of (cancer) stem cells.
  • ABCB1 and ABCG2 have different expression profiles in patient tumor samples.
  • Co-expressed in kidney, liver, and pancreas.

Goal in Cancer Treatment

  • Understand why some cancers don’t respond to chemotherapy and reverse drug resistance.
  • Find gene signatures to resensitize cancer cells to therapy.
  • Inhibit transporters responsible for drug resistance.
  • First ABC transporter (ABCB1) discovered in the 70s, cloned in the 87s then ABCG2 was discovered in the 90s and then ABCC1.

Clinical Trials Targeting ABC Transporters

  • Late 90s-2012: different trials to inhibit transporters, especially ABCB1 in acute myeloid leukemia.

Important Effects from Transporter Deletion

Effect of transporter deletion on plasma or brain. Table of prognosis of ABCB1, G2 and C1 in AML. ABCB1 was negatively associated with complete response. Important to predict resistance.

Clinical Trial Failures and Generation of Inhibitors

  • Different studies failed with 2000 patients.
  • Three generations of inhibitors:
    • 1st generation : not that specific and highly toxic for patients
    • 2sd and then a 3rd generation that were less toxic and more specific to the transporter.
  • 2010: clinicians suggesting "dismounting the MDR horse.