New targeted therapeutic agents have the potential to revolutionize how cancer is treated.
Side effects of chemotherapy, such as neutropenia, are a leading cause of treatment interruptions and dosing deductions. Interruptions and changes in treatment regimens have shown to negatively impact survival outcomes.
Non-targeted forms of chemotherapy are more limited in terms of how potent the medication can be. This is because the non-targeted chemotherapy can destroy both cancer and healthy cells. Targeted approaches allow oncologists to use more potent forms of chemotherapy while minimizing the impact on healthy cells.
While necessary for some cancer patients, non-targeted chemo can be especially harsh. Side effects vary based on the drug regimen and patient, but there's seemingly no shortage of side effects related to chemotherapy treatments.
The majority of cancer patients develop neutropenia during cancer treatment and it's the leading reason why cancer treatments need to end, be delayed, or dose levels of chemo need to be reduced.
Neutropenia is a lack of neutrophils, which are a type of white blood cell that are critical for fighting off infections. Patients with neutropenia are at a much higher risk for contracting an infection, requiring hospitalization, and changing or ending cancer treatment.
Next-generation chemo targets characteristics of cancers cells that differentiate them from healthy cells. This targeting can improve the efficacy against tumor cells and minimize damage to healthy cells
Chemotherapy with targeting capabilities has significant and distinct benefits, which include:
Delivering chemo to targets on tumors helps to minimize damage to healthy cells. This has the potential to cause fewer side effects and improve patient outcomes.
Attaching existing cytotoxic agents, such as taxanes or SN-38 (used by Trodelvy), to targeted antibodies or peptides allows for existing drugs to gain greater efficacy.
Peptide-Drug Conjugates (PDCs) and Antibody-Drug Conjugates (ADCs) are forms of targeted chemotherapy that feature either peptides or antibodies attached to cytotoxic agents. The cytotoxic drugs that are used in these conjugates are usually too toxic to be given by themselves. However, the conjugate allows the cytotoxic agent to be used safely in patients.
New targeted chemotherapy provides treatment options when other therapies aren't effective or simply don't exist yet. Targeted chemotherapy provides hope to patients that have refractory forms of cancer or have failed prior forms of treatment. Moving forward, targeted chemotherapy may become the first line of treatment.
Targeted chemotherapy targets proteins that control how cancer cells grow, divide, and spread. As researchers learn more about the DNA changes and proteins that drive cancer, they are better able to design promising treatments that target these proteins.
The development of targeted therapies requires the identification of good targets—that is, targets that play a key role in cancer cell growth and survival. Proteins that are present in cancer cells but not normal cells or that are more abundant in cancer cells are potential targets.
Targeted chemotherapy is designed to link to the target the drug was designed for. Once these drugs have attach to targets on the surface of cancer cells, the cells interact with the cytotoxic agents, causing them to die. Healthy cells that don’t have the target are less likely to be harmed.
While some targeted therapies have efficacy without internalization within the tumor, releasing cytotoxic agents inside the tumor can decrease the chances of side effects such as neutropenia and increase efficacy.
The following targets have been identified and have drugs already approved by the FDA:
These are examples of targets being researched, some with clinical trials already in progress:
Peptide-Drug Conjugates (PDCs) and Antibody-Drug Conjugates (ADCs) are forms of targeted chemotherapy that feature either peptides or antibodies attached to cytotoxic agents. A limited number have been approved by the FDA for use in cancer treatment, with many others currently being studied in clinical trials.
While FDA-approved ADCs provide improvements over standard chemotherapy for eligible patients, they have shortcomings that PDCs have the potential to overcome including:
Neutropenia is a common adverse event in cancer patients treated with antibody-drug conjugates (ADCs).
The off-target toxicities of ADCs are a result of the cytotoxic molecules released into the blood circulation prematurely.
ADCs are larger and less stable than PDCs, which makes ADCs more challenging for chemo internalization.
The complexity and cost of manufacturing ADCs is still an ongoing challenge.
The drug targets below don't have therapies approved by the FDA yet, but they appear particularly promising. These targets are used in ongoing clinical trials.
Goals for targeted chemotherapy using these new targets include:
The content below will grow over time and be updated as news develops:
Research from the University of Gothenburg, University of Limoges, L'Université du Québec à Montréal (UQAM), and Theratechnologies have identified sortilin as a promising new target for targeted chemotherapy.
The FDA granted a Fast Track designation to for the clinical trial of TH1902, a PDC targeting SORT1 for patients with advanced solid tumors. The trial is being led by M.D. Anderson Cancer Center .
Treatment options for triple negative breast cancer are still limited, which makes identifying new targets critical. FRα is expressed in a high percentage of triple negative breast cancers, as well as certain types of ovarian and lung cancer, and is a biomarker that's actively investigated.
Folate is an essential part of cell metabolism and as a result an overexpression of FRα may make tumors more likely to increase their growth and spread. As a result, targeted anti-FRα therapy may help to reduce cell growth.
"There are now several therapies directed at FRα which include monoclonal antibodies alone such as farletuzumab or as drug conjugates such as MOv18-IgG1 (and anti-FRα antibody conjugated with a Src inhibitor25), FRα engineered chimeric antigen receptor (CAR) T cells26 and a vaccine-based approach."
Zinc transporter LIV-1 is estrogen regulated and present in increased amounts in estrogen receptor–positive breast cancer as well as in tumors that spread to the lymph nodes. LIV-1 expression is found in most metastatic breast cancers, as well as in melanoma, and prostate, ovarian, uterine, and cervical cancers.
"SGN-LIV1A, or ladiratuzumab vedotin (LV), is a novel investigational humanized IgG1 antibody-drug conjugate (ADC) directed against LIV-1, which is highly expressed in breast cancer cells. LV mediates delivery of monomethyl auristatin E (MMAE), which drives antitumor activity through cytotoxic cell killing and induces immunogenic cell death (ICD)."