CANCER 2024

Over the last century, much has been done to prevent some cancers and to detect many malignancies before they have metastasized.

Most lung cancer deaths “are caused by smoking cigarettes or second hand smoke,”

In 1964, 42% of Americans were hooked on tobacco. Then the surgeon general officially told us that smoking cigarettes increases the risk of developing lung and laryngeal cancer and people listened. "The percentage of Americans who smoked dropped from 42% in 1964 (the peak year for smoking) to 18% in 2014”.

In 2020 cancer of the liver was still the third most common cause of cancer mortality in the world, and the livers of the majority of those affected were chronically infected by the hepatitis B or C virus---

When a woman giving birth has active chronic hepatitis B she often exposes her newborn to the virus. The infection -- the disease--however--can usually be prevented if the baby is given the hepatitis B vaccine shortly after it is born. If an unvaccinated newborn or child develops hepatitis B it commonly becomes chronic, lifelong problem.

In the 1980s, researchers developed effective vaccines for hepatitis B, and people should be able to prevent the chronic form of the disease. Unfortunately the World Health Organization estimates that only 18 percent of Africans have received three injections of the hepatitis B vaccine. "In 2022 WHO estimated that 254 million people were living with chronic hepatitis B and that there were 1.2 million new infections each year."

Hepatitis C is transmitted by transfusions, shared needles and sex. When adults are infected the viral infection becomes chronic 70 to 80 percent of the time. In 2019 experts concluded that year 6.2 million people were infected by the virus and it caused the death of 540 million.

Finding the virus that causes hepatitis C took 6 years of round the clock research, but in 1989 a group of researchers identified it. Ten years later Bartenshlager and others used a viral clone to construct segments of RNA, “replicons”, that allowed researchers to screen drugs that could potentially be used to treat hepatitis C. A few years later a Pharmasset, an anti-viral startup, developed a drug that almost always cures hepatitis C quickly with minimal side effects. Then the antiviral giant Gilead bought Pharmasset for $11billion. Gilead planned to charge about $80,000 fer each cure. The price was welcomed by the company’s stockholders, troubled health insurers, and was painful to many in the third world who had chronic hepatitis C.

Months before the FDA approved the drug one of the founders of Pharmasset was invited to Egypt. He helped the Egyptians buy some of the medication, Egyptian scientists reverse engineered it, and Egyptians started producing it.

In 2013 the FDA approved the drug for use in the U.S. and the Egyptian Patent Office (EGYPO) refused to grant a patent to Gilead. “Technical examination of the compound revealed that it is not novel chemically, and therefore does not fulfill the criteria of novelty and inventiveness, both of which are necessary for a pharmaceutical compound to be patented.” Without a patent for the drug, sofosbuvir, Gilead could not prevent an Egyptian pharmaceutical company from producing a generic version of the medication.

That year 14.7% of the people in Egypt had chronic hepatitis C, many were dying, and the president of Egypt, Abdel el-Sisi decided to act.

“In a public health campaign extraordinary for both its scale and its success, Egypt screened its entire population, brokered a deal for hugely discounted drugs and cured almost everyone with the virus. Then the country started providing the drug to other African countries.(1) Unfortunately worldwide the prevalence of hepatitis C remains high.

It was estimated that in 2019 there were 6.2 million new hepatitis C infections, 0.54 million HCV-related deaths, and 15.3 million DALYs--disability adjusted lost years.

Mammograms, colonoscopy, PSA testing for prostate cancer, and CAT scan screening of smokers are making a difference.

Infections with the human papillomavirus are usually transmitted sexually--when a person has “vaginal, anal, or oral sex with someone who has the virus, even if they don’t have signs or symptoms."

“Most HPV infections go away by themselves within 2 years. But HPV infections can last longer and can cause cancers of the cervix, vagina, penis, and back of the throat. Each year in this virus“ is responsible for about 36,000 cases of cancer in the U.S. in both men and women.” (CDC).

When the vaccine for the human papillomavirus is administered to 12 and 13 year olds, a girl’s risk of developing carcinoma of the cervix falls significantly. Etc.

Cancer is a genetic condition. We believe it starts when a cancer cell--a cell that reproduces rapidly and doesn't die-- is born --and not discovered and destroyed by T lymphocytes. Then the abnormal cell and its offspring duplicate and multiply and the malignant cells seem to live forever.

The original cancer cell (--in most cases--we believe) was the offspring of a line of cells that had over many generations acquired and passed a series of mutations on to their descendants. (“Some people inherit “faulty” or mutated genes that increase their risk of cancer, but most cancers develop because of a combination of chance and our environment.”) (2)

Localized cancers can usually be removed surgically. When a cancer has spread and is growing in one other location, the malignant cells in the other location can sometimes be radiated or completely removed surgically. (When a person with an otherwise surgically curable colon cancer has a single metastasis in the liver--and the solitary metastasis is resected –one of three people are cured.)

When a cancer has become wide spread doctors currently have three types of tools and treatments that can cure some tumors and control the growth of others. They are:

1. Chemotherapy and radiation therapy.

2. Immunotherapy;

3. Small molecules that block the action of an abnormal cell surface receptor.

T There are large numbers of protein receptors on the surface of most cells. One end the receptors protrudes--sticks out of the surface of the plasma membrane--the rest of the receptor protein penetrates the cells outer layer and exits the tissue layer inside the cell. When the outer part of a receptor is triggered by a signalling molecule, it chemically transmits a message to the inner cell. when activated some receptors tell cells to grow or multiply. Others tell cells to die.

Chemo: During the last half of the 20^th century doctors learned how to fight cancer with X-ray beams and toxic drugs that kill rapidly growing cells. In the early 1900s we doctors only had few chemo drugs to work with and we administered one drug at a time. As additional medications became available a few aggressive docs learned how to successfully use combinations of several drugs to destroy malignant cells. In his book The Emperor of Maladies, Siddhartha Mukherjee relates stories of the doctors who dared to use multiple toxic drugs at the same time, and they learned the combinations allowed them to cure some cancers and leukemias, and prolong the lives of many.

Immunotherapy: In the later part of the 20^th century doctors learned that an immune cell called the T lymphocyte attacks and destroys malignant cells--then a researcher in the U.S. and a researcher in Japan discovered instances where the T lymphocyte recognized the malignant cell and injected a poison---but the cancer cell produced an antidote and survived.

in the U.S. a researcher named Jim Allison worked out the structure of the T cell antigen receptor and became the head of a research lab at the University of California in Berkeley California. His lab worked on the relationship between the T cell and cancer. In animal studies, T cells seemed to recognize and attack cancer cells. They latched on and released a poison, a protein called CD28 that should have destroyed the malignant cell, but the cancer somehow survived. They learned that after the CD28 was released, another protein, CTLA-4, showed up in the cancer cell. Allison developed an antibody that blocked CTLA-4 and one of his fellows gave it to a mouse with cancer. A few days later, the cancer was gone.

After a number of experiments produced the same result, Allison realized our understanding of cancer biology was “backwards.” T lymphocytes, he hypothesized, recognized cancer cells. They latched on and injected a “poison” (CD28) that should kill the malignant cell. But cancer cells made an “antidote” (CTLA-4) that stopped the poison from working. His antibody blocked the antidote and allowed the poison made by T cells to kill the bad cells. Some of today’s cancer drugs block antidotes that cancer cells make-- and allow T cells to kill cancer cells.

In 2018 Jim Allison, a grizzled Texas researcher who loved playing the harmonica with Willie Nelson, and Tasuku Honjo, a Japanese researcher wearing a black haori coat and hakama trousers attended the Swedish Nobel ceremony-and jointly received the Nobel Prize in medicine for their efforts in creating medicines that blocked the antidote and enhanced the ability of T-lymphocytes to destroy certain cancers.

Elsewhere researchers dealt with the fact that T - lymphocytes are capable of destroying cancer cells, but they have trouble recognizing them. A number of researchers were instrumental in the development of CAR-T—a technique that allowed them to program T cells to recognize and destroy certain cancers. The process starts when blood is drawn from a vein and poured through an apheresis machine. The T lymphocytes are removed and the blood is returned to the person’s body. The T cells are taken to a lab where they are programmed to recognize a certain cancer. Weeks later the now-modified T cells are re-infused into the patient and they attack the malignancy.

1. (Genes for a chimeric antigen receptor are added to T cells. They tell the T cell to make a protein receptor that will exclusively bind to certain proteins on the patient’s cancer cells.

2. (Receptors are molecules--proteins in or on a cell. When they bind to a substance they cause the cell to react in a special way. When insulin binds to receptors on the surface of a certain cells it causes the cell to allow sugar to enter.

The CARs are chimeric receptors. (A chimeric animal could for example have the body of a turtle and the head of a dragon.) When these antigens are triggered they cause the T cell to react.) the process is very pricey.

Rituximab is one of several injectable antibodies that revolutionized the treatment of some lymphomas. It targets CD20, a unique protein that is only found on the surface of one kind of human cell, the B lymphocyte. The mice that make the antibody were genetically altered, and the antibodies they make are hybrids—chimeric—part mouse and part human. After rituximab is infused, it circulates and “tends to stick to the side of B cells that are rich in CD20. Natural killer cells then destroy up to 80% of a body’s B cells.” The initial drug was developed by a San Diego start-up called IDEC whose founders include several Stanford university researchers and Ivor Royston, a San Diego immunologist. We now know the antibody they developed is also useful in people with multiple sclerosis and a number of autoimmune and inflammatory diseases.

On May 10, 2023 researchers from Sloan Kettering Hospital published a study of 16 people with pancreatic cancer who were vaccinated with an individualized mRNA vaccine in an attempt to activate their T cells. From December 2019 to August 2021 surgeons at the institution had removed pancreatic cancers and shipped hunks of tissue to the BioNTech research lab in Europe. In Germany researchers analyzed the tumor, identified proteins that were unique to each cancer (neo-antigens), and created individualized MRNA vaccines that targeted the distinctive proteins. The vaccines contained up to 20 neoantigens suspended in lipoplex nanoparticles, and they were given intravenously. They assumed the people who received the vaccines would make antibodies -- but what would the T-lymphocytes do?

(“There are proteins that only wildly growing, genetically abnormal cells--cancer cells in the pancreas or colon secrete.” Jens Nielsen-researcher, Chalmers University of Technology Gothenburg, Sweden.

Two years after their initial cancer surgery half the patients had recurrent cancer of the pancreas and half did not have a recurrence. Time will tell whether or not this approach cures some people.

The third approach to wide spread cancer involves drugs, small molecules, that block--inhibit the action of one type of trans membrane cell receptors-- tyrosine kinase receptors.

Cells are born knowing how to perform certain functions. Kidney and liver cells know how to strain and cleanse our blood. Muscle cells know how to contract. Bodies use molecules (signals-"ligands") to influence the cells life, death and activity. Some of these signals are hormones like growth hormone or insulin. Other signals are molecules. The signals attach to a specific receptor that sticks out of the surface membrane of cells. (Most receptors are complex proteins that are embedded in the plasma membrane of the cell. One receptor end hangs out of the cell and the other end juts into the cytoplasm. There are hundreds of cell receptors. )

Visa vis cancer, the type of receptor that we attack is called a “Tyrosine kinase associated receptor." Some of these proteins play a role in a cells ability to survive, heal, grow, divide and die.” And some “govern the growth and metastasis of many cancers.”

The first and most successful Tyrosine Kinase inhibitor, was sold as a medication called imatinib or Gleevec.

Imatinib was the product of decades of research at the Ciba-Geigy lab in Basel, Switzerland, and was discovered by a research team chasing a dream, a theory, a hypothesis. Alex Matter, a Swiss MD, and Nick Lydon were trying to find a small molecule that would attach to an area on a cancer cell and stop it from growing.

Their search was based on staurosporine, a chemical that Japanese researchers had isolated from Streptomyces staurosporeus, a bacterium they found in a soil sample. Ten years after its discovery, staurosporine was shown to be a potent - but non-specific - inhibitor of a number of protein kinases, particularly tyrosine kinases. It also has a potent cytotoxic effect on cancer cells. The Geigy researchers knew that “Kinases possess at least one deep druggable pocket” on their outer surfaces. They looked for molecules that would bind to a druggable target and. as a result, would benefit the patient. They tried to create small molecules that would fit in the pocket and block the kinase.

Each part of the body is made up of cells. Within each of these small units, traffic is directed down various metabolic pathways by enzymes called kinases.At the appropriate time, kinases cause cells to “grow, shrink, and die.” Matter wondered if, in people with some cancers, one of the proteins that function as an “on” or “off” switch got stuck in the pro-growth position. Could that be the reason abnormal cells don’t die and keep growing? What if we could block a corrupting kinase without harming the other 90 or so known tyrosine kinases? Could we cure that cancer? That was the dream.

Locating the bad kinase and plugging it with the appropriate small molecule is a little like finding a needle in a hay stack. But that’s what the Swiss Geigy team lead by Alex Matter and Nick Lydon set out to do. (Matter was 12 years old when he began dreaming that he would one day be involved in the “discovery of important new medicines.”) In 1983, he became a Ciba researcher in Basel, the centuries-old city that straddles the Rhine just before the river bends and enters Germany.)

He and Lydon made various small alterations to staurosporine, created new molecules, and tested them one by one for toxicity and efficacy. A few seemed promising and the researchers gradually accumulated dozens of kinase blockers. The project took years and must have been quite costly. Geigy funded the studies “reluctantly.” Matter was told to keep investigating other approaches to cancer. The kinase program was supposed to be “very very small—hidden in plain sight.”

In the 1980s, Lydon went to Boston in search of a cancer that might be susceptible to one of his kinase inhibitors. He met Bryan Drucker, a lanky, soft-spoken physician from St. Paul, Minnesota, who had spent nine years at the Dana Farber Institute. Drucker was studying chronic myelocytic leukemia and was interested in Matter’s drug. Matter was unable to provide the chemical because lawyers for the Swiss company and the Dana Farber Institute “could not find agreeable terms.”

During the next few years, the drug remained in Switzerland. Then Drucker moved to Oregon, contacted Lydon, and requested the drug. When he visited the Oregon university lawyers and asked for permission to test a Swiss drug, his request seemed casual. No big deal. The university lawyers “humored” Drucker and gave him permission..

After he obtained the kinase inhibitors, Drucker tested them. The blocker caused chronic myelocytic leukemia (CML) cells in a Petri dish to die. Then Druker planted tumor cells in a mouse and gave the mouse the drug. This time the tumor got smaller.

Most cases of CML are caused by a genetic accident. The tips of two chromosomes have “broken off,” switched location, and fused. The resulting “hybrid” gene, called the Philadelphia chromosome, causes the abnormal cells to keep reproducing. The defect that causes the disease had been elucidated and explained a decade earlier by a hematologist named Janet Rowley.

In the absence of a bone marrow transplant, chronic myelocytic leukemia was usually lethal. If a person had an HLA identical sibling, and if they underwent a stem cell transplant, they subsequently had a 60 to 80 percent chance of surviving and being disease free five years out. Without someone else’s bone marrow, half of those affected were dead in three years, and fewer than one in five lasted 10 years.

But a dream was being realized. A small molecule could selectively inhibit an enzyme and control or cure cancer. Turning the protein into a drug a human could use required proving its safety in animals, then people. Several hundred million dollars needed to be spent before the company could market the medication. It would only help a few thousand people.

The first clinical trial of imatinib mesylate (Gleevec) took place in 1998, and Gleevec was amazingly effective. In 2001, the FDA approved the new medication and granted Novartis a five-year monopoly.

When it first came out, Novartis worried because most cancers eventually become resistant to therapy, but they were pleasantly surprised. Gleevec and a slightly altered later iteration “changed the natural course of the malignancy.” It didn’t cure chronic myelocytic leukemia, but it turned it into a chronic disease, a problem people were able to live with.

A 2015 study of people who had taken Gleevec for 10 years found that “82% of them were alive and progression-free. By 2018, “an estimated 8,430 people in the United States” were living with the diagnosis.

The inner workings of each cell are probably pre-programmed and are also controlled by proteins produced inside the cell in response to one of many genes. The DNA of each cell contains the same 20,000 genes and some of them are functional in every cell. Each gene is the blue print for one protein. 500 of the genes (apparently) can direct the cell’s ribosome to produce proteins called kinases. Kinases are enzymes that help speed up chemical reactions in a cell.” They act as “master switches that –within each cell-- turn some pathways on and others off. And they induce cells to grow, shrink, move, stop, or die.” (Mukherjee, the Emperor of Maladies.)

The activity of cells is also controlled by outside influencers---hormone, peptides, etc. I don’t know if any influencers actually enter cells, but I do know that many, if not all, influencers work by activating receptors--structures that have one end outside the cell and one end inside the cell.

An influencer does something to the end of the receptor that sticks out of the cell membrane, the message is passed through the receptor, and the other end of the receptor is chemically altered. Technically phosphates are transferred (The process of passing phosphates is called “phosphorylation”.) Adding the phosphate to certain amino acids “activates” a protein or an enzyme. (Think replacing the batteries in a flashlight or flipping a light switch and allowing electricity to flow to a light bulb.)

Example: An influencer called Insulin is released by the pancreas, flows through the blood and attaches to receptors on fat and muscle cells. “Like a key fits into a lock, insulin binds to receptors on the cell's surface, causing glucose transport proteins (GLUT4 molecules) to come to the cell's surface. The proteins then ferry the glucose into the cell.”

Receptor tyrosine kinases mediate responses to a large number of signals, including peptide hormones like insulin and growth factors like epidermal growth factor. The human genome has more than 500 protein kinases, cell surface proteins that play critical roles in cell signaling pathways involved in metabolism, injury responses, adaption, growth and differentiation.

Gleevec taught us that some aberrant protein kinases cause cancer cells to grow wildly. Blocking these kinases can stop the cell from growing and multiplying.

“Since the first tyrosine kinase inhibitor imatinib was approved to enter the market by the US Food and Drug Administration (FDA) in 2001, an increasing number of small-molecule targeted drugs have been developed for the treatment of malignancies. By 2020 89 small-molecule targeted anti-tumor drugs had been approved by the US FDA and the National Medical Products Administration (NMPA) of China.”

While most kinase inhibitors are anti-neoplastic (cancer) agents, a few are also used for benign conditions including macular degeneration (pegaptanib), rheumatoid arthritis (tofacitinib) and idiopathic pulmonary fibrosis (nintedanib). Generally, however, the side effect profile of kinase inhibitors are such that they are reserved for severe, progressive, debilitating or potentially fatal conditions.

The protein kinase inhibitors all have some degree of hepatotoxicity and many have been linked to cases of clinically apparent liver injury which can be severe and even fatal. Two protein kinase inhibitors (imatinib and nilotinib) have been linked to instances of reactivation of hepatitis B.

In recent decades the global pharmaceutical industry has discovered a number of small molecules and protein kinase inhibitors …. drugs that specifically target protein kinases and other proteins that are altered in cancer cells and that account for some of their abnormal growth.

Many of the protein kinases are cell surface receptors and act to initiate an intracellular pathway of activation after the receptor is engaged by an influencing molecule--typically a cytokine or growth factor. Inhibitors of these kinases are called protein kinase receptor inhibitors.

Unfortunately, over time tumors usually find a way around the block and eventually start growing again.

Crizotinib is a relatively new Pfizer drug that inhibits the kinase activity of a fusion protein called ALK-fusion non small lung cancer.” It often prevents tumor growth for a year or more before the tumor becomes resistant to therapy. The number of new cases of tumors with “ALK-fusion non small lung cancer” is about 9,000 per year in the U.S. and about 45,000 worldwide.

J. Jean Cui, the lead inventor of crizotinib, claims her team increased their chance of success by using structural chemistry rather than standard trial-and-error. The rational drug design method is also known as reverse pharmacology because the first step is to identify promising target proteins, which are then used for screening of small-molecule libraries.

Two impressive tyrosine kinases have recently reached the market:

One of them was developed by Turning Point Therapeutics. Called repotrectinib, it is a next-generation, potential best-in-class tyrosine kinase inhibitor (TKI) and it targets the ROS1 and NTRK oncogenic drivers of non-small cell lung cancer and other advanced solid tumors. “Although repotrectinib can overcome resistant mutations that other ROS1 inhibitors cannot overcome, the drug does not seem to have more side effects than other ROS1-targeted drugs,” said Luis Raez, M.D., director of the Thoracic Oncology Program at Memorial Cancer Institute in Florida. Its owner, Bristol Myers Squibb “expects” it to become a new standard of care for patients with the right genetic defect. It will probably also be quite pricy. In June 2022 Bristol Myers Squibb bought Turning Point for $4.1 billion.

The other newish promising tyrosine kinase inhibitor was developed in Japan and is called alectinib. Among patients with resected ALK-positive non small lung cancer-- stage IB, II, or IIIA-- adjuvant alectinib significantly improved disease-free survival as compared with platinum-based chemotherapy. (New England Journal of Medicine April 10 2024) https://www.nejm.org/doi/full/10.1056/NEJMoa2310532

In summary, the field of ALK-positive lung cancer has been one of the great success stories in the era of targeted therapies. In less than one decade from the initial discovery of ALK rearrangements in non small cell lung cancer, multiple targeted therapy agents have received regulatory approval by the U.S. FDA.

But we have not yet created a drug that will turn metastatic cancer into a chronic tolerable condition—we haven’t yet developed another Gleevec.

Scientists have also developed a number of small molecules that fight some cancers by blocking the action of certain vital proteins. example: PARP inhibitors:

PARP inhibitors often help stop the growth of ovarian cancer cells.

DNA repair is a collection of processes by which a cell identifies and corrects damage to the DNA molecules. Being able to repair DNA is vital to cell survival.

Normal cells have more than one DNA repair pathway. However, cancer cells often have defects in DNA repair pathways.

PARPs are families of proteins—enzymes. They are present in cells and are “involved in a number of cellular processes such as DNA repair and programmed cell death.” PARP inhibitors are small molecules that dock in one of the PARP catalytic pockets and trap PARP in sites where DNA is damaged. By blocking DNA repair pathways they prevent cell growth and can delay the re-emergence of metastatic ovarian cancer. https://pubmed.ncbi.nlm.nih.gov/10390360/

1.https://www.madamasr.com/en/2014/05/23/opinion/society/egypt-will-not-patent-new-hepatitis-c-drug/

https://pmc.ncbi.nlm.nih.gov/articles/PMC3702438/https://www.nytimes.com/2023/11/28/health/hepatitis-c-cure-egypt.html

https://www.nejm.org/doi/full/10.1056/NEJMoa0900212

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8848772/

2. https://www.cancerresearchuk.org/about-cancer/causes-of-cancer/inherited-cancer-genes-and-increased-cancer-risk/family-history-and-inherited-cancer-genes#:~:text=Being%20born%20with%20inherited%20faulty,a%20genetic%20predisposition%20to%20cancer

https://sciencenews.dk/en/researchers-map-the-unique-proteins-secreted-by-cancer-cells)

https:///www.khanacademy.org/science/ap-biology/cell-communication-and-cell-cycle/signal-transduction/a/signal-perception

https://www/.ncbi.nlm.nih.gov/pmc/articles/PMC7140093/

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728163/

http://www.satoshi-mura.info/staurosporine/index.html

https://www.ncbi.nlm.nih.gov/books/NBK548591/

https://www.nih.gov/news-events/news-releases/nih-study-shows-how-insulin-stimulates-fat-cells-take-glucose#:~:text=In%20response%2C%20the%20pancreas%20secretes,come%20to%20the%20cell's%20surface.