New Drugs for Cancer

The long development process of lab screening and animal tests is expensive and weeds out most compounds. Only about 0.1% of potential medicines eventually make it to clinical trials in human subjects.

The reasons medicines are screened out are many. Some drugs kill malignant cells but are not specific enough for the targets the scientists set for them or are poisonous. Others are unstable and would break down in any serious clinical use. Others may work at the cellular level but there is no way to get the medicine to the cells through administration to the body (e.g. oral, IV).

Once medicines make it to clinical trials, most of those are screened out too. For one reason or another the backers drop development and do not seek to advance the medicine to the next phase. Reasons include overly severe side effects or too many side effects or ineffectiveness of the medicine.

Dead ends

Antisense drugs generated quite a bit of excitement in the early 21st Century, but that excitement has faded. A targeted therapy, antisense agents switched off specific genes. The idea is that by inserting an oligonucleotide that essentially blocks the gene transcription process, the disease cannot proceed. There was hope they would be used for genetic disorders, including cancer. But no therapies have come even close to clinical use.

Stem cells are an area of research in rehabilitative therapy. Although they have generated excitement among scientists, few practical solutions have come out of the lab. A type of cell called Cancer Stem Cells (CSC) might be important in growth and metastasis of some types of cancers, but this idea has not been proven yet.

Some of the clinical trials have not focused on the disease of cancer but on the effect of new drugs on CSCs.  Stem cells are a difficult enemy; scientists suspect combination therapy might be required in order to prevent crosstalk among signaling pathways.

Future of Chemotherapy

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 medicine are small molecule drugs. They are often made by chemical synthesis or some are made by fermentation.

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. Under the categories immunotherapy and monoclonal antibodies, they offer greater specificity and fewer side effects.

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.

A 2018 review stated 150 kinase-targeted drugs are in clinical trials, with many more in laboratory research. 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.

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. 

How New are the New Drugs?

Most new drugs approved by the FDA aren’t totally new. They are variations or combinations of old drugs – new methods of delivery, etc. A survey of new drugs approved from 1989 to 2000 found only 35% were new molecular entities (NMEs). The rest were combinations with other drugs or differed from previously approved medicines in method of administration or dosage. The 1984 Hatch-Waxman Act allows the FDA to give market exclusivity to new medicines which are not NMEs and therefore cannot be patented.

New Immunotherapy

In recent years, development of new immunotherapy agents has revolutionized cancer treatment. These drugs induce or potentiate the anti-tumor activity of the immune system.

The immune system identifies tumors and triggers an anti-tumor response. Such response, however, is modulated by stimulating and inhibiting factors. The new immunomodulating agents work by slowing down the action of natural immune system inhibitors and by speeding up natural stimulatory factors. The novelty of this approach stems from the fact that the drug targets the host immune cells and not the tumor itself. Antibody-drug conjugates are related avenue of research that is yielding promising results. Following therapeutic and commercial successes, a lot of efforts are being put in the development of new ADCs. With milder side effects, ADCs promise to substantially expand the medical oncologist’s toolkit for fighting cancer.

More on immnotherapy.

Gene Therapy

Gene therapy has been talked about by futurists for years. The idea is that by changing the DNA in the body’s cells, the genetic cause of illness can be addressed. Strategies include inactivating a bad gene, changing a mutated gene to a healthy gene, and putting a new gene in the body to fight disease. Researchers are making progress in employing gene therapy against sickle cell anemia, connective tissue disorders, and retinal disease. Some gene therapy for cancer is have entered clinical use. The most advanced area in anti-cancer gene therapy is CAR-T therapies, chimeric antigen receptor T-cell, which involves genetic modification of T-cells removed from the patient and then re-introduced to the body. In 2017 the FDA approved tisagenlecleucel and axicabtagene ciloleucel which are CAR-T processes.

See more on notch inhibitors.

A Shortage of Test Patients

There is so much interest from pharmaceutical companies in developing new immunotherapy treatments and personalized therapy that experts worry there aren’t enough cancer patients to fill up the openings in clinical trials needed to test the new therapies.

Newly Approved Oncology Drugs

In 2018 the US Food and Drug Administration approved a bumper crop of 59 new drugs; 16 of these were for cancer. Here is a list of oncology drugs approved in recent years:

Medicine Trade Name Category Target
2015      
Palbociclib Ibrance kinase inhibitor metastatic breast cancer
Lenvatinib Lenvima kinase inhibitor differentiated thyroid cancer
Panobinostat Farydak HDAC inhibitor multiple myeloma
Dinutuximab Unituxin Monoclonal antibody neuroblastoma
Sonidegib Odomzo Hedgehog signaling pathway inhibitor locally advanced basal cell carcinoma
Trifluridine and tipiracil Lonsurf thymidine phosphorylase inhibitor (antimetabolite) colorectal cancer
Trabectedin Yondelis alkylating agent liposarcoma and leiomyosarcoma
Cobimetinib Cotellic kinase inhibitor advanced melanoma
Osimertinib Tagrisso kinase inhibitor non-small cell lung cancer
Daratumumab Darzalex monoclonal antibody multiple myeloma
Ixazomib Ninlaro Proteasome inhibitor multiple myeloma
Necitumumab Portrazza monoclonal antibody squamous non-small cell lung cancer
Elotuzumab Empliciti monoclonal antibody multiple myeloma
Alectinib Alecensa kinase inhibitor ALK-positive lung cancer
2016      
Venetoclax Venclexta BCL-2 Inhibitor chronic lymphocytic leukemia
Atezolizumab Tecentriq monoclonal antibody urothelial carcinoma
Olaratumab Lartruvo monoclonal antibody soft tissue sarcoma
Rucaparib Rubraca PARP inhibitor ovarian cancer
2017      
Avelumab Bavencio monoclonal antibody metastatic Merkel cell carcinoma
Niraparib Zejula PARP inhibitor epithelial ovarian, fallopian tube or primary peritoneal cancers
Durvalumab Imfinzi Monoclonal Antibody urothelial carcinoma
Neratinib maleate Idhifa Kinase inhibitor acute myeloid leukemia
Inotuzumab ozogamicin Besponsa Antibody drug conjugate acute lymphoblastic leukemia
Copanlisib Aliqopa PI3K inhibitor follicular lymphoma
Enasidenib Idhifa IDH2 inhibitor acute myeloid leukemia
Abemaciclib Verzenio kinase inhibitor metastatic breast cancers
Acalabrutinib Calquence kinase inhibitor mantle cell lymphoma
2018      
Lutetium Lu 177 dotatate Lutathera radioimmunotherapy conjugate gastroenteropancreatic neuroendocrine tumors
Binimetinib Mektovi kinase inhibitor metastatic melanoma
Encorafenib Braftovi kinase inhibitor metastatic melanoma
Ivosidenib Tibsovo IDH1 inhibitor acute myeloid leukemia
Mogamulizumab Poteligeo Monoclonal Antibody non-Hodgkin lymphoma
Moxetumomab pasudotox-tdfk Lumoxiti Monoclonal Antibody hairy cell leukemia
Duvelisib Copiktra PI3K inhibitor leukemia and lymphoma
Dacomitinib Vizimpro kinase inhibitor non-small-cell lung cancer
Cemiplimab-rwlc Libtayo Monoclonal antibody squamous cell carcinoma
Talazoparib Talzenna PARP Inhibitor breast cancer
Lorlatinib Lorbrena kinase inhibitor non-small cell lung cancer
Glasdegib Daurismo Sonic hedgehog pathway inhibitor acute myeloid leukemia
Larotrectinib Vitrakvi kinase inhibitor solid tumors (only the second tissue-agnostic oncology drug approved by FDA)
Gilteritinib Xospata kinase inhibitor acute myeloid leukemia
Calaspargase pegol-mkn Asparlas enzyme acute lymphoblastic leukemia
Tagraxofusp-erzs Elzonris conjugate of interferon and toxin blastic plasmacytoid dendritic cell neoplasm
2019      
Erdafitinib Balversa kinase inhibitor bladder cancer
Alpelisib Piqray PI3K inhibitor breast cancer
Polatuzumab vedotin Polivy antibody conjugate diffuse large B-cell lymphoma
Selinexor Xpovio selective inhibitor of nuclear export multiple myeloma
Darolutamide Nubeqa androgen receptor antagonist castration resistant prostate cancer
Entrectinib Rozlytrek kinase inhibitor NTRK-defect tumors; tissue-agnostic oncology drug