Future of Chemotherapy

Chemotherapy is only one of the three traditional modalities of cancer treatment – the others are radiation and surgery.  And combination therapy – chemotherapy plus radiation or surgery or both – is a common method oncologists use to address malignancies.  Therefore, if there is to be a “cure” for cancer in the future, it may not be a drug taken as a pill or  intravenously by itself.  For one thing, there are many types of cancer, and each is a different disease.  So even if a cure for one is developed, the same cure could be ineffective in another.  Secondly, there is a good chance that radiation and/or surgery will be involved.

Will we develop a Cure for Cancer?

We need to think about what a cure would look like.  The ideal cure would be a simple drug, with no side effects, that makes the cancer go away.  But what about a treatment that might last several months and require multiple trips to the hospital and for the patient to put up with unpleasant side effects and pain.  At the end of that treatment, if malignant cells cannot be detected, and if the disease does not return – hasn’t the cancer been “cured”?  Yes, by any definition of cure the cancer has been cured.   In the oncology world, people are reluctant to use the word cure because the reappearance of the cancer is common.  But by the standards of the commonplace use of that term, we have a cure right now.

At least for some cancers and some patients.  To be sure, cancer is still a big killer, but every year hundreds of thousands of Americans complete a course of treatment and do not have further cancer.

The Susan G. Komen charity sponsors 5K races around the country – these are called the “Race for the Cure”.  Komen is trying to raise money, and many cancer charities appeal to donors’ desire to see a cure.  Komen focuses on breast cancer, which has a high survival rate.  Many patients do recover from breast cancer although many thousands die every year.

If the history of the war on cancer is any guide, it is likely that the battle will be one of attrition without a clear cure – a “finish line” in the long struggle.

If we can’t cure cancer, another desirable outcome would be to convert it to a condition we can manage in the long run and keep from being fatal to the patient.

Funding

Most basic research is funded by government entities, and that is not likely to change in the foreseeable future.  These government agencies are all over the world and channel money to universities and other research institutes.  An article in the Journal of Oncology Practice in 2014 stated that 85 percent of basic research is funded by government funds.  It is unclear exactly what scope this entails, but it probably refers to research done in the United States.  Searches for viable treatments are more often conducted by for-profit pharmaceutical companies.  Those companies reportedly spend only 1.3 percent of revenues on basic research but on the order of 10 percent on clinical trials.  We are unaware of nonprofit organizations that develop oncology drugs.

Big Molecules and Small Molecules

The drug discovery industry today divides potential new therapeutic compounds into two categories: small molecule and biologics. Remember when you were in chemistry class and you drew out the structure of molecules? Any molecule you can draw on a piece of paper is a “small molecule”. Most medicines are small molecule drugs, also called low molecular weight (LMW) drugs. They are often made by chemical synthesis; some are made by fermentation.  The signal transduction inhibitors including kinase inhibitors are small molecule drugs.

Biologics, also called biopharmaceuticals, are enormous molecules. If you know anything about proteins you know they can have thousands of atoms in a molecule. Biologics are often, but not always, proteins. They are often referred to as biotech drugs. They are produced by living cells. As therapeutics, biologics first appeared in oncology medicine in the 1990s. Immunotherapy, whereby the patient’s immune system is stimulated or supplemented, makes use of biologics.

A larger share of new oncology drugs are biologic than drugs for other diseases. Going forward, industry observers anticipate new combinations of existing therapeutic products and new solutions such as cancer vaccines, nucleic-acid therapies, and new antibodies.

Targeted therapy and precision therapy

The near-term prospects are dominated by targeted therapies, which more directly fight the cancer than the blunt tools of cytotoxic drugs.  It is estimated that 90 percent of pivotal trials for oncology drugs are directed at molecular targets.

Immunotherapy makes use of monoclonal antibodies designed to attach to certain biomarkers found on malignant cells.  Between 2015 and 2020 – a six year period – 19 new unconjugated MAbs were approved by the FDA for cancer therapy.  Additionally, seven new MAb conjugates were approved.

Hundreds of kinase inhibitors are in clinical trials, with many more in the laboratory research stage.  Indeed, kinase inhibitors are the focus of a quarter of all new pharmaceutical research.  Kinase inhibitors are in development for other diseases besides cancer.  Other types of signal transduction inhibitors are also being developed.  This is probably the most active branch of medical oncology today.

Even more precise precision medicine

For years molecular biologists have known how to sequence the genome and to characterize tumors at a genetic level.  However, those tools have for the most part stayed in the lab where they are part of both basic and translational research.  They are not employed in the clinic.

It is hoped that precision medicine will be able to harness those tools for patient treatment, and there has been some advancement in the area.  Faster and cheaper ways to characterize tumors – next-generation sequencing (NGS) – allow doctors to find therapeutic targets to go after with precision agents.

It’s not always easy however, as cancers are complex even at a genetic level and it’s rarely just one mutation that makes the malignancy.  So a precise treatment may not do the trick.  And cancers continue to mutate.  So precision treatment is not a miracle cure even though it can be valuable.

Adoptive Cell Therapy, including Chimeric antigen receptor (CAR) T-cell, is taking techniques from biotech labs and using them directly on patientsCAR-T involves removing a patient’s T-cells from his or her blood and inserting new genetic material in the laboratory.  The cells are then “amplified” – caused to multiply in lab glassware, and then reinjected back into the patient’s bloodstream.  The new genes given to the T-cells help them make two types of proteins.  In a sense the patient’s own cells are engineered to fight the cancer.

Other types of targeting

 Synthetic lethality is another area of interest to scientists and PARP inhibitors work that way.

Another interesting and exciting trend is the development of tumor-agnostic medicines.

Small interfering RNAs have attracted the attention of researchers. Also called short interfering RNAs (siRNAs) or silencing RNAs, these compounds  can switch off expression of genes, and they have thus proven valuable in figuring out which genes regulate what biochemistry. Could we find siRNAs that turn cancer off – stop the genetic drivers of tumor growth? That is the idea, and some laboratory and animal experiments have shown promise. But there has been no success in developing treatments for human cancer patients.

Targeted protein degradation has been proposed as a therapeutic strategy specifically for proteins that are not amenable to conventional pharmacological methods. Proteolysis-targeting chimeras (PROTACs) are the first class of drug developed with this approach in mind.  None have become available for use in patients yet.

mRNA vaccines are of interest, especially after their success against COVID-19.  RNA is a nucleic acid that plays a major role in cell function.  Some RNA is “messenger” RNA, abbreviated mRNA, transmits information from the DNA to the mechanism in the cell that makes proteins.

Early work with mRNA vaccines show they have good safety profiles and that pharmaceutical companies can make them in large quantities.  Scientists point to several ways mRNA vaccines could help: (1) when encoded for tumor-associated antigens, (2) to produce personalized vaccines, and (3) to transfect patient-derived cells in vitro and infuse the manipulated cells back into the patient.  BioNTech has announced they are in Phase 2 trials of vaccines for patients with colorectal cancer, and it is estimated that over 20 mRNA cancer vaccines have gone into clinical trials.

PROTACs – PROteolysis TArgeting Chimeras are combinations of proteins.  The active site of one of the proteins binds to the protein associated with the disease.  The  other half of the PROTAC binds to ubiquitin ligase, which plays a part in the cellular waste disposal system.  Because the disease protein is then connected to ubiquitin ligase, the cell’s proteasome removes it and destroys it.  “Proteolysis” means “breaks down proteins,” and drug developers hope that this system will allow them to get at disease proteins they cannot reach with antibodies or traditional small molecule drugs.  Scientists are looking at this technology for therapeutics in oncology and other parts of medicine.

Anti-evolution therapies

Cancer cells continue to mutate in a tumor.  This is partly why cancer is so hard to defeat. It continues to change inside the body – microevolution in action. Scientists are trying to approach with “anti-evolution” therapies. None have reached the trial phase yet; the development is a high-tech affair employing “big data” and feedback from imaging systems that show cancer spread in the body during treatment. Scientists involved are talking about a triple-drug attack and speak of blocking APOBEC proteins, which other therapies do not do.

A place for traditional chemo?

Nobody is saying old-style cytotoxic drugs will disappear in the near future.  Despite the downsides of those drugs, they are still widely used and will continue to be used.  Indeed, although many oncologists are keen to try targeted therapies such as signal transduction inhibitors, they often give patients both the new drugs and the old ones.

However, few cytotoxic drugs are in development, and not many have been approved in recent years.

Prospects – chances of success

There have been a lot of advances in basic research into cancer biology, but the successes in translational research have been somewhat disappointing.  Scientists now understand many genetic alterations and how they connect to molecular drivers (signal transducers, growth factors).  Rational drug designers take this information and attempt to devise compounds or antibodies to stop the drivers, but these don’t often work.

Although the 2010s saw a big increase in the number of NME’s approved by the FDA, most worked by similar mechanisms to previously approved drugs.  While there is value in having multiple drugs in a class, the chances of making significant gains against cancer is enhanced by having new “first-in-class” drugs.  A study showed that 38 percent of approvals in 2009 were for compounds that work by novel mechanism, but only 12 percent of approvals in 2020 were.  So while the sheer number of new drugs coming onto the market is up considerably, the picture on new mechanisms is not so bright.