As a physician-scientist have been involved in preclinical drug discovery and clinical development Phase I-III oncology therapeutics for over 30 years - this is an important question. The field as evolved considerably largely because of deeper understanding of human cancer biology, pharmacology, genomics/gene expression, improved treatments, innovations in medicinal and biological chemistry, and the development of better laboratory testing methods and models. It is clear that the development and use of increasingly correlated and relevant animal models and preclinical testing are essential for advancing new discoveries in cancer therapeutics in immuno-oncology, targeted therapies, cytotoxic therapies, and others (eg., agonists, cytokine modulation, and overcoming drug resistance in various forms).
We don't use or rely on primates for drug discovery very much at all - almost exclusively now only for relevant species (most commonly cynomolgus monkeys; chimpanzees are no longer allowed for many years now) to human PK/PD safety, starting dose/dose-range testing of investigational new drugs in certain settings.
The vast majority of testing and model systems involve patient derived xenografts (PDX) which intrisically have heterogenous tumor cell populations, and human cell-line derived xenograft human tumors (CDX) that are used for in vitro and in vivo testing. Most PDX and CDX testing for antitumor efficacy and PK/PD are conducted in certain strains of immuno-deficient mice, and some cases rodents.
It would be highly impractical to sit, monitor and wait for tumors to spontaneously arise in primates (or in other species) for cancer drug treatment research - one would have to monitor these animals for new tumors all the time (eg., screening, CT/MRI scanning, biomarker testing for months or years) which would take too much time and be very costly to perform. The other problem is that non-human primate tumors, as well as murine/rodent and canine tumors are not genetically and biologically the same as human tumors. So, there is a significant limitation in testing these types of tumors and the results would not transfer well to humans with cancer. The other consideration is that primate studies are very expensive to conduct - so we use them very carefully and on a limited and very focused basis to arrive at safe starting doses, identify the safe dose range, and preliminary PK/PD profile for human studies of investigational cancer therapies.
There are much better methods that have been developed in the last 30+ years for this purpose. The big issue/caveat with any animal testing is that the testing in the lab does not always correlate 1:1 with humans, in fact it's only a highly variable partial correlation in most cases (more than 95% of the time), but in recent years much has been discovered that help to close this gap somewhat further - particularly in the immuno-oncology and targeted therapy fields. There are more sophisticated methods and models that have been developed and are used.
One major factor driving all of this focus on better animal and laboratory models and testing methods in new cancer drug research and development is that survival outcomes for the most common types of cancer has significantly improved in the past 30 years. The cancer death rate for men and women combined fell 32% from its peak incidence in the US in 1991 to 2019. So now, we are working on the harder to treat cancers. Please see Cancer Statistics 2022 from the American Cancer Society and look at the mortality reductions in 1991 to 2019 in the US in the most common cancer types.
Another major factor driving the underlying science and methods for laboratory testing in new cancer drug development is the fact that the evolution of and advances in cancer treatment are very rapid - as well as the understanding of tumor biology is deepening further every day. The lab testing and animal systems we used 5 or 10 years ago would not be capable of identifying new and better drugs today. These areas concommitantly and exponentially have driven the demand for more predictive animal models and testing methods; particularly in the last 8-10 years.
What we do today with relevant animal models and testing systems for generally approaching new cancer drug discovery involves a primary focus on discovering and targeting new biologic/molecular targets that control cancer cell behavior - eg., abnormal proliferation/growth, resistance to drug-mediated apoptosis, resistance to drug treatment (many different types) - especially resistance to immune mediated cell killing, metastatic behavior, reducing cancer drug resistance and driver mutations, etc. At a fundamental level, today we look at gene regulation and expression levels to do all of this, since this information is what gives us a genomic tumor signature to work with as well as a means to prove a new drug modifies, normalizes or kills the abnormal signature cell population. To do this, we start in the lab with human cancer genomic expression information and identify when the correlation between the target's presence in a cancer cell type/disease population is over expressed, and how the target of interest operates mechanistically in terms of regulating the cancer cell population's biology and how it can be targeted in best mode for maximal effect and maximal safety/tolerabiltiy (eg., monoclonal antibody, ADC, small molecule, bispecific antibody, CAR-T, CRISPR/gene editing, other cell therapy, etc.).
The selected mode of therapy (any of the foregoing areas above - antibodies, small molecules, bispecifics, BiTEs, CAR-T, CRISPR, etc. - which govern/control the route and schedule of administration) is tested in the laboratory in vitro and in vivo in relevant (partially or fully humanized) test systems and animal models using human tumor cell lines or human tumors from patients, eg., CDX and PDX models. Some animal models (particularly in mice) involve the use of human "knock-in" (gene insertion) and "knock-out" (eg., target gene or immediate proximity partner gene(s) deletion) to investigate and determine the relevance and precision of a specific target and it's downstream pharmacodynamic effects. CRISPR and CAR-T both involve cellular reprogramming the immune system to recognize and kill tumor cells by either genetic recombination/alteration of the abnormal genome (CRISPR) or by using tumor antigen recognition and T-cell (and in some cases NK reprogramming and stimulation).
These testing methods and systems play an important role in the discovery and development of new innovations in cancer treatment because the older systems would miss the critical newly discovered elements in cancer biology that are oncogenic drivers and/or resistance factors to current treatment. What we can do now in the lab has a huge impact on clinical development to better exploit the science for the benefit of patients.
There are many other factors to consider in the discovery and development of new cancer treatment involving complex biology, chemistry, formulation, drug delivery, safety and tolerability, pharmacology (the sum total time- and dose-dependent behavior of absorbtion, distribution, metabolism and elimination of a drug and its metabolite(s)), optimal dosing, and identifying which patients will benefit the most from such therapy.
DrFredCancerRandD t1_iwb7bxb wrote
Reply to How do medical researchers obtain lab animals with diseases like specific forms of cancer which arise spontaneously? Do they raise thousands of apes and hope some eventually develop the disease? by userbrn1
As a physician-scientist have been involved in preclinical drug discovery and clinical development Phase I-III oncology therapeutics for over 30 years - this is an important question. The field as evolved considerably largely because of deeper understanding of human cancer biology, pharmacology, genomics/gene expression, improved treatments, innovations in medicinal and biological chemistry, and the development of better laboratory testing methods and models. It is clear that the development and use of increasingly correlated and relevant animal models and preclinical testing are essential for advancing new discoveries in cancer therapeutics in immuno-oncology, targeted therapies, cytotoxic therapies, and others (eg., agonists, cytokine modulation, and overcoming drug resistance in various forms).
We don't use or rely on primates for drug discovery very much at all - almost exclusively now only for relevant species (most commonly cynomolgus monkeys; chimpanzees are no longer allowed for many years now) to human PK/PD safety, starting dose/dose-range testing of investigational new drugs in certain settings.
The vast majority of testing and model systems involve patient derived xenografts (PDX) which intrisically have heterogenous tumor cell populations, and human cell-line derived xenograft human tumors (CDX) that are used for in vitro and in vivo testing. Most PDX and CDX testing for antitumor efficacy and PK/PD are conducted in certain strains of immuno-deficient mice, and some cases rodents.
It would be highly impractical to sit, monitor and wait for tumors to spontaneously arise in primates (or in other species) for cancer drug treatment research - one would have to monitor these animals for new tumors all the time (eg., screening, CT/MRI scanning, biomarker testing for months or years) which would take too much time and be very costly to perform. The other problem is that non-human primate tumors, as well as murine/rodent and canine tumors are not genetically and biologically the same as human tumors. So, there is a significant limitation in testing these types of tumors and the results would not transfer well to humans with cancer. The other consideration is that primate studies are very expensive to conduct - so we use them very carefully and on a limited and very focused basis to arrive at safe starting doses, identify the safe dose range, and preliminary PK/PD profile for human studies of investigational cancer therapies.
There are much better methods that have been developed in the last 30+ years for this purpose. The big issue/caveat with any animal testing is that the testing in the lab does not always correlate 1:1 with humans, in fact it's only a highly variable partial correlation in most cases (more than 95% of the time), but in recent years much has been discovered that help to close this gap somewhat further - particularly in the immuno-oncology and targeted therapy fields. There are more sophisticated methods and models that have been developed and are used.
One major factor driving all of this focus on better animal and laboratory models and testing methods in new cancer drug research and development is that survival outcomes for the most common types of cancer has significantly improved in the past 30 years. The cancer death rate for men and women combined fell 32% from its peak incidence in the US in 1991 to 2019. So now, we are working on the harder to treat cancers. Please see Cancer Statistics 2022 from the American Cancer Society and look at the mortality reductions in 1991 to 2019 in the US in the most common cancer types.
Another major factor driving the underlying science and methods for laboratory testing in new cancer drug development is the fact that the evolution of and advances in cancer treatment are very rapid - as well as the understanding of tumor biology is deepening further every day. The lab testing and animal systems we used 5 or 10 years ago would not be capable of identifying new and better drugs today. These areas concommitantly and exponentially have driven the demand for more predictive animal models and testing methods; particularly in the last 8-10 years.
What we do today with relevant animal models and testing systems for generally approaching new cancer drug discovery involves a primary focus on discovering and targeting new biologic/molecular targets that control cancer cell behavior - eg., abnormal proliferation/growth, resistance to drug-mediated apoptosis, resistance to drug treatment (many different types) - especially resistance to immune mediated cell killing, metastatic behavior, reducing cancer drug resistance and driver mutations, etc. At a fundamental level, today we look at gene regulation and expression levels to do all of this, since this information is what gives us a genomic tumor signature to work with as well as a means to prove a new drug modifies, normalizes or kills the abnormal signature cell population. To do this, we start in the lab with human cancer genomic expression information and identify when the correlation between the target's presence in a cancer cell type/disease population is over expressed, and how the target of interest operates mechanistically in terms of regulating the cancer cell population's biology and how it can be targeted in best mode for maximal effect and maximal safety/tolerabiltiy (eg., monoclonal antibody, ADC, small molecule, bispecific antibody, CAR-T, CRISPR/gene editing, other cell therapy, etc.).
The selected mode of therapy (any of the foregoing areas above - antibodies, small molecules, bispecifics, BiTEs, CAR-T, CRISPR, etc. - which govern/control the route and schedule of administration) is tested in the laboratory in vitro and in vivo in relevant (partially or fully humanized) test systems and animal models using human tumor cell lines or human tumors from patients, eg., CDX and PDX models. Some animal models (particularly in mice) involve the use of human "knock-in" (gene insertion) and "knock-out" (eg., target gene or immediate proximity partner gene(s) deletion) to investigate and determine the relevance and precision of a specific target and it's downstream pharmacodynamic effects. CRISPR and CAR-T both involve cellular reprogramming the immune system to recognize and kill tumor cells by either genetic recombination/alteration of the abnormal genome (CRISPR) or by using tumor antigen recognition and T-cell (and in some cases NK reprogramming and stimulation).
These testing methods and systems play an important role in the discovery and development of new innovations in cancer treatment because the older systems would miss the critical newly discovered elements in cancer biology that are oncogenic drivers and/or resistance factors to current treatment. What we can do now in the lab has a huge impact on clinical development to better exploit the science for the benefit of patients.
There are many other factors to consider in the discovery and development of new cancer treatment involving complex biology, chemistry, formulation, drug delivery, safety and tolerability, pharmacology (the sum total time- and dose-dependent behavior of absorbtion, distribution, metabolism and elimination of a drug and its metabolite(s)), optimal dosing, and identifying which patients will benefit the most from such therapy.