A quote from Voltaire (1760) highlights skepticism towards doctors and their treatments:
> "Doctors are men who prescribe medicines of which they know little, to cure diseases of which they know less, in human beings of whom they know nothing."
Paracelsus (1538) emphasized the importance of dosage in distinguishing a poison from a remedy:
> "All substances are poisonous, there is none that is not a poison; the right dose differentiates a poison from a remedy."
Cancer Mortality Trends
US Male Cancer Mortality Rates (1930 - 2020):
Figure 1 illustrates trends in age-adjusted cancer death rates by site in males in the US from 1930-2020.
Despite downward mortality trends, therapeutic outcomes are sometimes minimal.
Many cancer treatment methods are based on practices predating the 1970s.
Lung cancer: Only a 12% increase in 5-year survival rates from 1970 to 2020.
Colorectal cancer: General decrease in patient deaths, but minimal change in death rates for advanced cases.
Enhanced Treatment Effectiveness
Current efforts seek improved diagnostics to enhance treatment effectiveness.
Cancer treatment has often followed a "cart blanche" approach.
More informed treatments using improved diagnostics will allow for proper targeting of various cancer subtypes:
Indolent Tumors: Benign prognosis; low invasive and metastatic potential.
Highly Aggressive Tumors
Intermediate Tumors: Potential to disseminate.
Differential Treatment Strategies Based on Tumor Subtype
Pancreatic Islet Tumor:
90% 5-year progression-free survival.
Surgery carries a high risk of mortality.
Pancreatic Exocrine Adenocarcinoma:
5% 5-year progression-free survival.
Potential Therapeutic Targets
Abnormal Mass
Cell Process:
Division
Apoptosis
Differentiation
Metastasis
Immune system
Effective Treatments Standing the Test of Time
Surgery
Radiotherapy
Chemotherapy
Surgical Removal
Surgical removal of abnormal cells.
May also be used as a preventative measure or to better diagnose, stage (how advanced?), make more accessible to other treatments, or relieve symptoms.
Types:
Basic: Incision and removal
Cryo-
Electro-
Laser
Mohs – layered skin cancer removal
Laparoscopic
Robotic
Natural Orifice: Unconventional
Mastectomy
In 1894, William Halsted published Mastectomy Technique.
"Radical Mastectomy": Removal of the entire breast affected by tumor growth.
Advanced Imaging and Surgery
Advanced imaging tools can now identify exact location and size.
Magnetic Resonance Imaging of breast tissue.
Better-informed surgery options now consider lumpectomies.
Lumpectomy and Radiotherapy
Lumpectomy patients receiving adjuvant radiotherapy were shown to have a 50% reduced rate of subsequent mastectomy within 10 years following surgery.
Lobectomy
Lobe of the lung affected by tumorigenic growth is completely removed.
Commonly used for non-small cell lung cancer.
Colonoscopy and Polypectomy
Colonoscopy allows identification of at-risk polyps.
Polypectomy refers to the removal of these polyps.
Radiotherapy can be more targeted compared to system-wide chemotherapy.
Chemotherapy
Chemicals Generally Form DNA Adducts
Nitrosamines from smoked foods can alkylate guanine.
This alkylation can disrupt DNA function.
Chemotherapy Targets Dividing Cells
Function: Induces DNA damage during replication, subsequently triggering apoptosis.
Classes:
Alkylating Agents
Antimetabolites
Organic Types
Side Effects
Consequence of cell type target
Hair follicles, stomach epithelia, & hematopoietic cells are rapidly dividing
Hair loss, ulcers, anemia
Chemotherapy: A Brief History
Referenced in the Emperor of Maladies documentary.
Chemotherapy Quandaries
Why do some cytotoxins target specific types of cells?
How do cancer cells develop resistance?
Cytotoxins and Tumor Cell Dependencies
Various cytotoxins target specific tumor cell dependencies.
Ovarian cancer cells deficient in homologous DNA repair mechanisms are more prone to cytotoxin Cisplatin, which causes DNA cross-links requiring homologous DNA repair.
Some cancer cells lack G2/M checkpoints, allowing the passage of all cells into M phase despite DNA damage from cytotoxins.
G2/M Checkpoint
Treatment of Human Hepatoma cells without a G2/M checkpoint leads to mitotic catastrophe.
Nuclei eventually fragment into micro nuclei, eventually resulting in apoptosis.
Mechanisms of Anti-Tumor Selectivity
cyclophosphamide: detoxified by ALDH in normal bone marrow
cladribine: detoxified by non-hematopoietic cell types
taxol/paclitaxel: high proliferation index, other mechanisms unknown
cisplatin (DNA-damaging agents): high proliferation index, high sensitivity to apoptotic stimuli
PARP inhibitors (DNA-damaging agents): intact p53 function in testicular germ-cell tumors, inability to halt cell cycle advance in response to DNA damaged, defective homology-directed repair, various types of defective DNA repair
Multi-Drug Treatment Protocols
A combination of cytotoxins eventually were employed to target multiple tumor cell dependencies.
FOLFOX: fluorouracil, leucovorin, oxiplatin (pyrimidine analog, folic acid antagonist, DNA cross-linking) - colorectal cancer
TIP: paclitaxel, ifosfamide, platinum agent cisplatin (microtubule antagonist, alkylating, DNA cross-linking) - testicular cancer
Mechanisms of Acquired Resistance to Anti-Cancer Therapies
Multi-drug resistance: increased expression of drug export pumps
Pan-drug resistance: unknown
Drug detoxification: enzymatic detoxification of drug molecule, failure of tissue to convert pro-drug into active form
Acquired drug resistance: refuge of cancer cells in drug-protected anatomical sites, refuge of cancer cells in an anatomical site that provides protective trophic signals, massive stromalization, emergence of mutant, structurally altered cellular target, amplification of gene encoding targeted protein, emergence of cells bearing alterations in genes whose products are functionally redundant with drug target, loss of drug importer, passage through an EMT , activation of anti-apoptotic regulators, Physiological activation of compensatory adaptive mechanisms
Resistance to EGF-R inhibition: up-regulation of IGF-1R signaling, amplification of Met gene, mutational activation of a ras pathway gene, cell state changes, including conversion from non-small-cell to small-cell lung cancer
Resistance to Bcr-Abl inhibition: amplification of Bcr-Abl gene, drug target site mutations in Abl, blast cell transition
Cancer Treatment Checkpoint
Indolent Tumors
Indolent tumors are benign and best removed through surgery (B).
Specific Therapies Targeting Molecular Pathways
Inhibition of Oncogenic pathway
Activation or rescue of tumor suppressor function
Genetic Lesion Targeting
Differentiation Pathway Targeting
Angiogenesis Targeting
Combinatorial Treatment
A diverse heterogeneous tumor cell landscape requires a diverse approach.
Stratification of Breast Tumor Genetics
The expression of 70 bioinformatically determined prognostic genes was analyzed in 295 primary breast cancer tumors from women 53 years and younger diagnosed with the disease.
The Kaplan Meier plot was generated from 151 breast cancer patients whose survival was tracked for the duration of 10 years following diagnosis.
Stratification of Diffuse Large B-Cell Lymphomas (DLBCLs)
DLBCLs are stratified into 3 subtypes:
Primary Mediastinal B-Cell Lymphomas (PMBCLs)
Germinal-Center B-Cell (GCB) DLBCLs
Activated B-Cell-Like (ABC) DLBCLs
Considerations for Targeting a Molecular Mechanism in a Subset
Drugs are usually low molecular weight compounds that are mostly biochemical inhibitors, not enhancers.
Restoring functions of large proteins such as tumor suppressors is logistically impossible.
Targets must be druggable, having domains usually catalytic clefts within their structure that can form strong and specific interactions with low molecular weight molecules.
Should yield substantial therapeutic indices, killing or affecting more tumor cells relative to the normal cells.
Potential Targeting of Downstream Signaling Elements to Inhibit Tumor Growth
PI3-Kinase
bcr-abl and Imatinib (Gleevec)
Imatinib competitively binds to the kinase site and inhibits protein activity.
Gleevec aka imatinib disables kinase activity.
Remission observed in 96% of early-stage patients.